Bicyclic aryl sphingosine 1-phosphate analogs

ABSTRACT

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphin-gosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

BACKGROUND

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokesa variety of cellular responses by stimulation of five members of theendothelial cell differentiation gene (EDG) receptor family. The EDGreceptors are G-protein coupled receptors (GPCRs) and on stimulationpropagate second messenger signals via activation of heterotrimericG-protein alpha (G_(α)) subunits and beta-gamma (G_(βγ)) dimers.Ultimately, this S1P-driven signaling results in cell survival,increased cell migration and, often, mitogenesis. The recent developmentof agonists targeting S1P receptors has provided insight regarding therole of this signaling system in physiologic homeostasis. For example,the immunomodulator, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane1,3-diol), that following phosphorylation, is an agonist at 4 of 5 S1Preceptors, revealed that affecting S1P receptor activity influenceslymphocyte trafficking. Further, S1P type 1 receptor (S1P₁) antagonistscause leakage of the lung capillary endothelium, which suggests that S1Pmay be involved in maintaining the integrity of the endothelial barrierin some tissue beds, S1P type 4 receptors (S1P₄) are expressed mainly inleukocytes, and specifically S1P₄ mediates immunosuppressive effects ofS1P by inhibiting proliferation and secretion of effector cytokines,while enhancing secretion of the suppressive cytokine IL-10. See, forexample, Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which isincorporated by reference in its entirety. S1P type 5 receptors (S1P₅)are exclusively expressed in oligodendrocytes and oligodendrocyteprecursor cells (OPCs) and are vital for cell migration. Stimulation ofS1P₅ inhibits OPC migration, which normally migrate considerabledistances during brain development. See, for example, Novgorodov, A. etal., (2007) FASEB J. 21: 1503-1514, which is incorporated by referencein its entirety.

S1P has been demonstrated to induce many cellular processes, includingthose that result in platelet aggregation, cell proliferation, cellmorphology, tumor-cell invasion, endothelial cell chemotaxis andangiogenesis, For these reasons, S1P receptors are good targets fortherapeutic applications such as wound healing, tumor growth inhibition,and autoimmune diseases.

Sphingosine-1-phosphate signals cells in part via a set of Gprotein-coupled receptors named S1P₁, S1P₂, S1P₃, S1P₄, and S1P5(formerly EDG1, EDG5, EDG3, EDG6 and EDG8). The EDG receptors areG-protein coupled receptors (GPCRs) and on stimulation propagate secondmessenger signals via activation of heterotrimeric G-protein alpha(G_(α)) subunits and beta-gamma (G_(βγ)) dimers. These receptors share50-55% amino acid sequence identity and cluster with three otherreceptors (LPA₁, LPA₂, and LPA₃ (formerly EDG2, EDG4 and EDG7) for thestructurally related lysophosphatidic acid (LPA).

A conformational shift is induced in the G-Protein Coupled Receptor(GPCR) when the ligand binds to that receptor, causing GDP to bereplaced by GTP on the α-subunit of the associated G-proteins andsubsequent release of the G-proteins into the cytoplasm. The α-subunitthen dissociates from the αγ-subunit and each subunit can then associatewith effector proteins, which activate second messengers leading to acellular response. Eventually the GTP on the G-proteins is hydrolyzed toGDP and the subunits of the G-proteins reassociate with each other andthen with the receptor. Amplification plays a major role in the generalGPCR pathway. The binding of one ligand to one receptor leads to theactivation of many G-proteins, each capable of associating with manyeffector proteins leading to an amplified cellular response. Generally,compounds can switch from antagonists to agonist depending on what Gprotein is downstream of the receptor. When G_(q) is downstream acompound targeting the S1P₄ receptor can act as an antagonist. It ispossible that with a different G protein (G_(i)) downstream an agonistcompound may be an agonist.

S1P receptors make good drug targets because individual receptors areboth tissue and response specific. Tissue specificity of the S1Preceptors is desirable because development of an agonist or antagonistselective for one receptor localizes the cellular response to tissuescontaining that receptor, limiting unwanted side effects. Responsespecificity of the S1P receptors is also of importance because it allowsfor the development of agonists or antagonists that initiate or suppresscertain cellular responses without affecting other responses. Forexample, the response specificity of the S1P receptors could allow foran S1P mimetic that initiates platelet aggregation without affectingcell morphology.

Sphingosine-1-phosphate is formed as a metabolite of sphingosine in itsreaction with sphingosine kinase and is stored in abundance in theaggregates of platelets where high levels of sphingosine kinase existand sphingosine lyase is lacking, S1P is released during plateletaggregation, accumulates in serum, and is also found in malignantascites. Reversible biodegradation of S1P most likely proceeds viahydrolysis by ectophosphohydrolases, specifically the sphingosine1-phosphate phosphohydrolases. Irreversible degradation of S1P iscatalyzed by S1P lyase yielding ethanolamine phosphate, and hexadecenal.

SUMMARY

Currently, there is a need for novel, potent, and selective agents thatare agonists of the S1P receptor having enhanced potency, selectivity,and oral bioavailability. In addition, there is a need in the art foridentification of, as well as the synthesis and use of, such compounds.

In one aspect, a compound can have formula (I):

In formula (I), A¹ can be —CX¹═, —C(X¹)₂—, —N═, —NX¹—, —O—, —S—, or abond; A² can be —CX²═, —C(X²)₂—, —N═, —NX²—, —O—, or —S—; A³can be—CX³═, —C(X³)₃—, —N═, —NX³—, —O—, —S—, or a bond; A⁴can be —CX⁴═,—C(X⁴)₂—, —N═, —NX⁴—, —O—, —S—, or a bond; A⁵can be —CX⁵═, —C(X⁵)₂—,—N═, —NX⁵—, —O—, or —S—; A⁶ can be —CX⁶═, —C(X⁶)₂—, —N═, —NX⁶—, —O—,—S—, or a bond; A⁷ can be —C(R³)═, —C(R³R^(f))—, or —NR³—; and A⁸can be—C(—W-Cy)=, —C(—W-Cy)(R^(f))—, or —N(—W-Cy)-.

B¹can be

and B²can be

In formula (I), no more than 1of A¹, A³, A⁴, and A⁶is a bond; B¹andB²are not both simultaneously

and no more than 4 ring atoms of A¹-A⁸ and B¹-B² are N, O, or S.

Each of X¹, X², X³, X⁴, X⁵, and X⁶, independently, can be hydrogen,halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl,halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl,aminoacyl, —N(R^(f)R^(g)), —N(R^(f))SO₂R^(g), —SO₂R^(f),—S(O)₂N(R^(f)R^(g)), —CO₂R^(f), trialkylamino, aryl, or heteroaryl.

W can be —C(R^(f)R^(g))—, —N(R^(f))—, —O—, —S—, —S(O)—, or —S(O)₂—.

Cy can be cycloalkyl, spirocycloalkyl, cycloalkenyl, spirocycloalkenyl,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl. Cy can beoptionally substituted by 1-6 substituents selected from the groupconsisting of halo, hydroxy, nitro, cyano, —N(R^(f)R^(g)), alkyl,haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy,cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy,acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl,heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl,aryl, or heteroaryl.

R³can be -L¹-J-L²-T¹.

L¹ can be —C(O)—, —S(O)₂—, —N(R^(f))C(O)—, —N(R^(f))—, —C(R^(f)R^(g))—,—C(R^(f)R^(g))—C(R^(f)R^(g))—, or a bond.

J can be —[C(R^(f)R^(g))]_(n)—, —N(R^(f))—[C(R^(f)R^(g))]_(n)—, or abond, wherein each n, independently, can be an integer from 0to 5; or Jcan be

where each of D¹ and D³, independently, can be

D² can be —[C(R^(f)R^(g))]_(k), —[C(R^(f)R^(g))]_(k)—N(R^(f))—,—[C(R^(f)R^(g))]_(k)—O—, —N(R^(f))—, or —N(R^(f))—[(CR^(f)R^(g))]_(k)—.D⁴ can be —[C(R^(f)R^(g))]_(m)—. k can be 1 or 2; and m can be 0, 1, 2,or 3. No more than 2 ring atoms of D¹-D⁴ can be N or O.

L² can be —C(R^(f)R^(g))—, —C(R^(f)G)-, —C(G)₂-,—C(R^(f)R^(g))—C(R^(f)R^(g))—, —C(R^(f)R^(g))—C(R^(f)G)-,—C(R^(f)R^(g))—C(G)₂-, or a bond.

At least one of L¹, J, and L² can be other than a bond.

T¹ can be —C(O)(OR^(f)), —C(O)N(R^(f))S(O)₂R^(f), tetrazolyl,—S(O)₂OR^(f), —C(O)NHC(O)—R^(f), —Si(O)OH, —B(OH)₂, —N(R^(f))S(O)₂R^(f),—S(O)₂NR^(f), —O—P(O)(OR^(f))OR^(f), or —P(O)₂(OR^(f)).

Each G, independently, can be hydrogen, hydroxy, a halogen, ortrifluoromethyl.

Each R^(f) independently, can be hydrogen, hydroxy, halo, alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl or NH₂. Each of alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl and heterocycle can be optionally substituted with 1 to 5substituents independently selected from the group consisting of halo,oxo, —CN, —CHO, —CG₃, —OH, —NO₂, alkyl, —OCG₃, alkoxy, cycloalkoxy,cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl,alkylsulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

Each R⁸, independently, can be hydrogen, hydroxy, halo, alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,or heterocyclyl. Each of alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl and heterocycle can be optionally substituted with 1 to 5substituents independently selected from the group consisting of halo,oxo, —CN, —CHO, —CG³, —OH, —NO₂, alkyl, —OCG₃, alkoxy, cycloalkoxy,cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl,alkylsulfonyl, alkylaminosulfonyl, can be dialkylaminosulfonyl.

The compound can be in the form of a pharmaceutically acceptable salt.

In some circumstances, A⁷ can be —CR³═, A⁸ can be —C(—W-Cy)=, B¹ can be

and B² can be

Of A¹-A⁶ , 0, 1, or 2 ring atoms of A¹-A⁶ can be N. The remaining ringatoms of A¹-A⁶ can each be C. A¹ can be —CX¹═, A² can be —CX²═, and A⁶can be —CX⁶═. A³ can be —CX³═, A⁴ can be CX⁴═, and A⁵ can be —CX⁵═.

In some circumstances, A¹ can be —CX¹═, A² can be —CX²═, A⁶ can be—CX⁶═, A⁸ can be —C(—W-Cy)=, B¹ is

B² can be

and A³, A⁷ , A⁴, and A⁵, can be, respectively: —NX³—, —C(R³R^(f))—, abond, and —C(X⁵)₂—; —C(X³)₂—, —NR³—, —C(X⁴)₂—, and —C(X⁵)₂—; —C(X³)₂—,—C(R³R^(f))—, —NX⁴—, and —C(X⁵)₂—; —N═, —CR³═, —CX⁴═, and —CX⁵═, —N═,—CR³═, —N═, and —CX⁵═; —CX³═, —CR³═, —N═, and —CX⁵═; —N═, —CR³═, —CX⁴═,and —N═; —CX³═, —CR³═, —CX⁴═, and —N═; —CX³═, —CR³═, —N═, and —N═;—NX³—, —CR³═, a bond, and —CX⁵═; or —CX³═, —CR³═, a bond, and —NX⁵—.

In some circumstances, A³ can be —CX³═, A⁴ can be —CX⁴═, A⁵ can be—CX⁵═, A⁷ can be —CR³═, B¹ can be

B² can be

and A², A¹, A⁸, and A⁶, can be, respectively: —CX²═, —CX¹═, —C(—W-Cy),and —N═; —CX²═, —N═, —C(—W-Cy), and —N═; —NX²—, —CX¹═, —C(—W-Cy)=, and abond; —NX²—, a bond, —C(—W-Cy)=, and —CX⁶═; or —CX²═, a bond,—C(—W-Cy)=, and —NX⁶—.

In some circumstances, each ring atom of A¹, A², A⁵-A⁸ and B¹-B² is C,and each of A³ and A⁴ is, independently, C or N. L¹ can be—C(R^(f)R^(g))— and J can be —NR^(f)— or

-   -   wherein    -   each of D¹ and D³ , independently, is

-   -   D² is —[C(R^(f)R^(g))]_(k—, —[C(R) ^(f)R^(g))]_(k)—N(R^(f))—,        —[C(R^(f)R^(g))]_(k)—O—, —N(R^(f))—, or        —N(R^(f))—[(CR^(f)R^(g))]_(k)—; and    -   D⁴ is —[C(R^(f)R^(g))]_(m)—;    -   wherein k is 1 or 2; and m is 0, 1, 2, or 3;    -   provided that no more than 2 ring atoms of D¹-D⁴ are N or O.        Each R^(f) and R^(g), independently, can be hydrogen or alkyl.        T¹ can be —C(O)(OR^(f)). T¹ can be        —C(O)N(R^(f))S(O₂R^(f)),—O—P(O)(OR^(f))OR^(f), —P(O₂)(OR^(f)),        tetrazolyl or —S(O)₂OR^(f). X⁶ can be an electron withdrawing        group. X⁶ can be halo, alkyl, or haloalkyl. Each G,        independently, can be fluoro or hydroxy.

In some circumstances, Cy can have the formula:

Z¹ can be a bond, —[C(R^(d)R^(e))]_(x)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Z² can be a bond, —[C(R^(d)R^(e))]_(y)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Z³ can be a bond, —[C(R^(d)R^(e))]_(z)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Each of x, y, and z, independently, can be 1, 2, or 3.

Each R^(d), and each R^(e), independently, can be hydrogen, halo,hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl.

R^(1a) and R^(1b), independently, can be hydrogen, halo, hydroxy, nitro,cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl,cycloalkyl alkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy,heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl,cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl,alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl,R^(1a) and R^(1b), when taken together, can be C₂-C₅ alkylene or C₂-C₅alkenylene.

R^(2a) and R^(2b), independently, can be hydrogen, halo, hydroxy, nitro,cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy,heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl,cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl,alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

R^(1a) and R^(2a), when taken together, can be C₁-C₅ alkylene or C₂-C₅alkenylene.

R^(1a), R^(1b), R^(2a) and R^(2b) can be each, independently,substituted with 0-5 substituents selected from halo, hydroxy, nitro,cyano, —NR^(f)R^(g), or —CO₂R^(f).

R^(1a) and R^(2a) can be both hydrogen. Z¹ can be —CH₂CH₂—. Z² can be—CH₂—. Z³ can be a bond.

R^(1b) can be fluoro, chloro, bromo, iodo, methyl, triflurormethyl,ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl,isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl,cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy,1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, orcyclohexyloxy.

In some circumstances, W is O, Z¹ is —[C(R^(d)R^(e))]_(x), Z² is—[C(R^(d)R^(e))]_(y)—, and Z³ is —[C(R^(d)R^(e))]_(z)—. In somecircumstances, X²is methyl. In some circumstances, W is —O—. In somecircumstances, each ring atom of A¹-A⁸ and B¹-B² is C. In somecircumstances, each ring atom of A¹-A³, A⁵-A⁸ and B¹-B² is C, and A⁴ isN. In some circumstances, each ring atom of A¹-A², A⁴-A⁸ and B¹-B² is C,and A³ is N. The compound can be in the form of a pharmaceuticallyacceptable salt.

In some circumstances, A² can be —CX²═, and X² is fluoro, chloro, bromo,methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl orbutyl.

In some circumstances, A¹ can be CH; A² can be —CX²═, and X² is fluoro,chloro, bromo, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl,isopropyl or butyl. A³ can be CH; A⁴ can be CH; A⁵ can be CH; A⁶ can beCH; A⁷ can be C(R³); A⁸ can be C(—W-Cy); B¹ can be

and B² can be

Each ring atom of A¹, A², A⁵-A⁸ and B¹-B² is C, and each of A³ and A⁴is, independently, C or N. L¹ can be —C(R^(f)R^(g))— and J can be—NR^(f)— or

-   -   wherein    -   each of D¹ and D³, independently, is

-   -   D² is —[C(R^(f)R^(g))]_(k)—, —[C(R^(f)R^(g))]_(k)—N(R^(f))—,        —[C(R^(f)R^(g))]_(k)—O—, —N(R^(f))—, or        —N(R^(f))—[(CR^(f)R^(g))]_(k)—; and    -   D⁴ is —[C(R^(f)R^(g))]_(m)—;    -   wherein k is 1 or 2; and m is 0, 1, 2, or 3;    -   provided that no more than 2 ring atoms of D¹-D⁴ are N or O.        Each R^(f) and R^(g), independently, can be hydrogen or alkyl.        T¹ can be —C(O)(OR^(f)). T¹ can be —C(O)N(R^(f))S(O)₂R^(f)),        —O—P(O)(OR^(f))OR^(f), —P(O₂)(OR^(f)), tetrazolyl or        —Si(O)₂OR^(f). X⁶ can be an electron withdrawing group. X⁶ can        be halo, alkyl, or haloalkyl. Each G, independently, can be        fluoro or hydroxy.

In some circumstances, Cy can have the formula:

Z¹ can be a bond, —[C(R^(d)R^(e))]_(x)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Z² can be a bond, —[C(R^(d)R^(e))]_(y)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Z³ can be a bond, —[C(R^(d)R^(e))]_(z)—, —CR^(d)═CR^(e)—, —O—, or—NR^(f)—.

Each of x, y, and z, independently, can be 1, 2, or 3.

Each R^(d), and each R^(e), independently, can be hydrogen, halo,hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl.

R^(1a) and R^(1b), independently, can be hydrogen, halo, hydroxy, nitro,cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy,heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl,cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl,alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl.R^(1a) and R^(1b), when taken together, can be C₂-C₅ alkylene or C₂-C₅alkenylene.

R^(2a) and R^(2b), independently, can be hydrogen, halo, hydroxy, nitro,cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl,heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy,heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl,cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl,alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

R^(1a) and R^(2a), when taken together, can be C₁-C₅ alkylene or C₂-C₅alkenylene.

R^(1a), R^(1b), R^(2a), and R^(2b) can be each, independently,substituted with 0-5 substituents selected from halo, hydroxy, nitro,cyano, —NR^(f)R^(g), or —CO₂R^(f).

R^(1a) and R^(2a) can be both hydrogen. Z¹ can be —CH₂CH₂—. Z² can be—CH₂—. Z³ can be a bond.

R^(1b) can be fluoro, chloro, bromo, iodo, methyl, triflurormethyl,ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl,isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl,cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy,1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, orcyclohexyloxy.

In some circumstances, W is O, Z¹ is —[C(R^(d)R^(e))]_(x)—, Z² is—[C(R^(d)R^(e))]_(y)—, and Z³ is —[C(R^(d)R^(e))]_(z)—. In somecircumstances, X² is methyl. In some circumstances, W is —O—.

In another aspect, a pharmaceutical composition includes apharmaceutically acceptable carrier and a compound of formula (I), asdefined above.

In another aspect, a method for prevention or treatment of apathological condition or symptom in a mammal, wherein the activity ofsphingosine 1-phosphate receptors is implicated and agonism of suchactivity is desired includes administering to said mammal an effectiveamount of a compound of formula (I).

In another aspect, a method for prevention or treatment of apathological condition or symptom in a mammal, wherein the activity S1Plyase implicated and inhibition of the S1P lyase is desired includesadministering to said mammal an effective amount of a compound offormula (I).

In another aspect, a method for prevention or treatment of apathological condition or symptom in a mammal, wherein the activity ofsphingosine 1-phosphate receptors is implicated and antagonism of suchactivity is desired includes administering to said mammal an effectiveamount of a compound of formula (I).

In another aspect, the pathological condition can be multiple sclerosis,autoimmune diseases, chronic inflammatory disorders, asthma,inflammatory neuropathies, arthritis, transplantation, Crohn's disease,ulcerative colitis, lupus erythematosis, psoriasis, ischemia-reperfusioninjury, solid tumours, tumour metastasis, diseases associated withangiogenesis, vascular diseases, pain conditions, acute viral diseases,inflammatory bowel conditions, insulin or non-insulin dependantdiabetes, inhibited cell migration, over-proliferation and secretion ofeffector cytokines, or lack of secretion of the suppressive cytokineIL-10.

In another aspect, the compound exhibits S1P₁ agonist activity. Inanother aspect, the compound exhibits S1P₁ agonist activity and issubstantially free of S1P₃ agonist and antagonist activity.

In another aspect, the compound exhibits S1P₅ antagonist activity. Inanother aspect, the compound exhibits S1P₅ agonist activity.

In another aspect, the compound exhibits S1P₄ antagonist activity. Inanother aspect, the compound exhibits S1P₄ agonist activity.

In another embodiment, the invention is directed to the examples havingformula (I), pharmaceutically acceptable salts thereof, or when theexample having formula (I) is a salt, a free base of that salt.

The compound of formula (I) can be a compound of formula (IIa)-(IId):

a compound of formula (IIIa)-(IIIg):

a compound of formula (IVa)-(IVc):

a compound of formula (Va)-(Vc):

or a compound of formula (VIa)-(VIc);

In certain circumstances, the compound is of formula (IIa), (IIIa) or(IIIb).

The details of one or more embodiments are set forth in the accompanyingdescription below. Other features, objects, and advantages will beapparent from the description and from the claims.

DETAILED DESCRIPTION

The following abbreviations are used herein; S1P,sphingosine-1-phosphate; S1P₁₋₅, S1P receptor types 1-5; GPCR, G-proteincoupled receptor; SAR, structure-activity relationship; EDG, endothelialcell differentiation gene; EAE, experimental autoimmuneencephalomyelitis; NOD non-obese diabetic; TNFα, tumor necrosis factoralpha; HDL, high density lipoprotein; and RT-PCR, revere transcriptasepolymerase chain reaction.

The values listed below for radicals, substituents, and ranges, are forillustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. Thedisclosed compounds include compounds of formula I having anycombination of the values, specific values, more specific values, andpreferred values described herein.

The term “halogen” or “halo” includes bromo, chloro, fluoro, and iodo.The term “haloalkyl”, refers to an alkyl radical bearing at least onehalogen substituent, non-limiting examples include, but are not limitedto, chloromethyl, fluoroethyl, trichloromethyl, or trifluoromethyl andthe like.

The term “C₁-C₂₀ alkyl” refers to a branched or linear alkyl grouphaving from one to twenty carbons. Non-limiting examples include, butare not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, oroctyl and thelike.

The term “C₂-C₂₀ alkenyl”, refers to an olefinically unsaturatedbranched or linear group having from two to twenty carbon atoms and atleast one double bond. Typically, C₂-C₂₀ alkenyl groups include, but arenot limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl,hexenyl, pentenyl, hexenyl, heptenyl, or octenyl and the like.

The term (C₂-C₂₀)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl,and the like.

The term “(C₁-C₁₀)alkoxy” refers to an alkyl group attached through anoxygen atom. Examples of (C₁-C₁₀)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy, and the like.

The term “(C₃-C₁₂)cycloalkyl” refers to a cyclic alkyl group, such as,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl, and the like. Cyloalkyl groups includebicyclic groups such as decalinyl, bridged bicyclic groups such asnorbornyl or bicyclo[2.2.2]octyl, tricyclic, bridged tricyclic such asadamantyl, or spiro-linked bicyclic or tricyclic groups.

The term “(C₆-C₁₄)aryl” refers to a monocyclic, bicyclic, or tricycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl,indenyl, or anthracyl, and the like.

The term “aryl(C₁-C₂₀)alkyl” or “arylalkyl” or “aralkyl” refers to analkyl group substituted with a mono or bicyclic carbocyclic ring systemhaving one or two aromatic rings including, a group such as phenyl,naphthyl, tetrahydronaphthyl, indanyl, or indenyl, and the like.Non-limiting examples of arylalkyl include benzyl, or phenylethyl, andthe like.

The term “(C₁-C₁₄)heterocyclic group” refers to an optionallysubstituted mono- or bicyclic carbocyclic ring system containing one,two, three, or four heteroatoms (optionally in each ring) wherein theheteroatoms are oxygen, sulfur, and nitrogen.

The term “(C₄-C₁₄)heteroaryl” refers to an optionally substituted mono-or bicyclic cyclic ring system containing one, two, or three heteroatoms(optionally in each ring) wherein the heteroatoms are oxygen, sulfur, ornitrogen. Non-limiting examples of heteroaryl groups include furyl,thienyl, or pyridyl, and the like.

The term “phosphate analog” and “phosphonate analog” comprise analogs ofphosphate and phosphonate wherein the phosphorous atom is in the +5oxidation state and one or more of the oxygen atoms is replaced with anon-oxygen moiety, including for example, the phosphate analogsphosphorothioate, phosphorodithioate, phosphoroselenoate,phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate,phosphoramidate, or boronophosphates, and the like, including associatedcounterions, e.g., H⁺, NH₄ ⁺, Na⁺, or K⁺, and the like if suchcounterions are present.

The term “alpha-substituted phosphonate” includes phosphonate(—CH₂PO₃H₂) groups that are substituted on the alpha-carbon such as—CHFPO₃H₂, —CF₂PO₃H₂, —CHOHPO₃H₂, or —C═OPO₃H₂) and the like.

The term “pharmaceutically acceptable carrier” includes any of thestandard pharmaceutical carriers, such as a phosphate buffered salinesolution, hydroxypropyl beta-cyclodextrins (HO-propyl betacyclodextrins), water, emulsions such as an oil/water or water/oilemulsion, and various types of wetting agents. The term also encompassesany of the agents approved by a regulatory agency of the U.S. Federalgovernment or listed in the U.S. Pharmacopeia for use in animals,including humans.

The term “pharmaceutically-acceptable salt” refers to salts which retainthe biological effectiveness and properties of the disclosed compoundsand which are not biologically or otherwise undesirable. In many cases,the disclosed compounds are capable of forming acid or base salts byvirtue of the presence of amino or carboxyl groups or groups similarthereto.

The term “prodrug” refers to a compound that is converted underphysiological conditions, e.g., by solvolysis or metabolically, to acompound that is pharmaceutically active, such as a compound of formula(I). A prodrug may be a derivative of a compound of formula (I) thatcontains a carboxylic or phosphoric acid ester or amide moiety that maybe cleaved under physiological conditions. A prodrug containing such amoiety may be prepared according to conventional procedures, forexample, by treatment of a compound of this invention containing anamino, amido or hydroxyl moiety with a suitable derivatizing agent, forexample, a carboxylic or phosphoric acid halide or acid anhydride, or byconverting a carboxyl moiety to an ester or amide. Metabolites of thecompounds of formula (I) may also be pharmaceutically active as well.

An “effective amount” means an amount sufficient to produce a selectedeffect. For example, an effective amount of an S1P receptor agonist isan amount that decreases the cell signaling activity of the S1Preceptor.

The disclosed compounds can contain one or more asymmetric centers inthe molecule. In accordance with the present disclosure any structurethat does not designate the stereochemistry is to be understood asembracing all the various optical isomers (e.g., diastereomers andenantiomers), as well as mixtures thereof (such as a racemic mixture).The compounds can be isotopically-labeled compounds, for example,compounds including various isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, iodine, or chlorine.

The disclosed compounds may exist in tautomeric forms and the inventionincludes both mixtures and separate individual tautomers. For example,the following structure:

is understood to represent a mixture of the structures:

as well as

An “S1P modulating agent” refers a compound or composition that iscapable of inducing a detectable change in S1P receptor activity in vivoor in vitro (e.g., at least 10% increase or decrease in S1P activity asmeasured by a given assay such as the bioassay described in the examplesand known in the art. “S1P receptor,” refers to all of the S1P receptorsubtypes (for example, the S1P receptors S1P₁, S1P₂, S1P₃, S1P₄, orS1P₅), unless the specific subtype is indicated.

It will be appreciated by those skilled in the art that the disclosedcompounds having chiral centers may exist in and be isolated inoptically active and racemic forms. It is to be understood that thedisclosed compounds encompass any racemic, optically active orstereoisomeric form, or mixtures thereof. It is well known in the arthow to prepare such optically active forms (for example, resolution ofthe racemic form by recrystallization techniques, synthesis fromoptically-active starting materials, by chiral synthesis, orchromatographic separation using a chiral stationary phase) and how todetermine S1P agonist activity using the standard tests describedherein, or using other similar tests which are well known in the art. Inaddition, some compounds may exhibit polymorphism.

Potential uses of an S1P receptor agonist, and S1P₁ receptor typeselective agonists particularly, include, but are not limited to,prevention or treatment of a pathological condition or symptom in amammal. For example, the condition can include asthma, inflammatoryneuropathies, arthritis, lupus erythematosis, psoriasis,ischemia-reperfusion injury, solid tumours, tumour metastasis, diseasesassociated with angiogenesis, vascular diseases, pain conditions, acuteviral diseases, or insulin and non-insulin dependant diabetes. Thecondition can alter lymphocyte trafficking as a method of treatment forneuropathic pain, inflammation-induced pain (e.g., where prostaglandinsare involved) or treatment of autoimmune pathologies such as uveitis,type I diabetes, rheumatoid arthritis, chronic inflammatory disorders,inflammatory bowel diseases (e.g., Crohn's disease and ulcerativecolitis), multiple sclerosis, and in drug-eluting stents. Additionaluses can include treatment of brain degenerative diseases, heartdiseases, cancers, or hepatitis C. See, for example, WO 2005/085295, WO2004/010987, WO 03/097028, and WO 2006/072562, each of which isincorporated by reference in its entirety. A class of S1P agonistcompounds are described in provisional U.S. Application No. 60/956,111,filed Aug. 15, 2007, and PCT/US2008/073378, filed Aug. 15, 2008, each ofwhich is incorporated by reference in its entirety.

Potential uses of an S1P receptor antagonist, and S1P₅ receptor typeselective antagonists particularly, include, but are not limited to,prevention or treatment of a pathological condition or symptom in amammal. For example, the condition can include inhibited cell migrationof oligodendrocyte precursor cells (OPCs). In another example, an S1P₅receptor type selective antagonist may not induce lymphopenia, therebyachieving partial efficacy without immunosuppression.

Potential uses of an S1P receptor antagonist, and S1P₄ receptor typeselective antagonists particularly, include, but are not limited to,prevention or treatment of a pathological condition or symptom in amammal.

“Treatment” of multiple sclerosis includes treating various forms of thedisease including relapsing-remitting, chronic progressive, and the S1Preceptor agonists/antagonists can be used alone or in conjunction withother agents to relieve signs and symptoms of the disease as well asprophylactically.

In addition, the disclosed compounds can be used for altering lymphocytetrafficking as a method for prolonging allograft survival, for exampletransplantation including solid organ transplants, treatment of graftvs. host disease, bone marrow transplantation, and the like.

In addition, the disclosed compounds can be used to inhibit autotaxin.Autotaxin, a plasma phosphodiesterase, has been demonstrated to undergoend product inhibition. Autotaxin hydrolyzes several substrates to yieldlysophosphatidic acid and sphingosine 1-phosphate, and has beenimplicated in cancer progression and angiogenesis. Therefore, S1Preceptor agonist pro-drugs of the disclosed compounds can be used toinhibit autotaxin. This activity may be combined with agonism at S1Preceptors or may be independent of such activity.

Disclosed compounds can be useful for inhibition of sphingosine kinase(i.e., of sphingosine kinase I, sphingosine kinase II, or both).Sphingosine kinase is an intracellular enzyme that catalyzes theformation of S1P from sphingosine and a nucleotide triphosphate (e.g.,ATP). Inhibition of sphingosine kinase can reduce the formation of S1Pand thereby reduce the supply of S1P available to activate signaling atS1P receptors. Accordingly, sphingosine kinase inhibitors can be usefulin modulating immune system function. Therefore, the disclosed compoundscan be used to inhibit sphingosine kinase. This inhibition could be inconcert with S1P receptor activity, or be independent of activity at anyS1P receptor.

In addition, disclosed compounds can be useful for inhibition of S1Plyase. S1P lyase is an intracellular enzyme that irreversibly degradesS1P. Inhibition of S1P lyase disrupts lymphocyte trafficking withconcomitant lymphopenia. Accordingly, S1P lyase inhibitors can be usefulin modulating immune system function. Therefore, the disclosed compoundscan be used to inhibit S1P lyase. This inhibition could be in concertwith S1P receptor activity, or be independent of activity at any S1Preceptor.

In addition, disclosed compounds can be useful as antagonists of thecannabinoid CB₁ receptor. CB₁ antagonism is associated with a decreasein body weight and an improvement in blood lipid profiles. The CB₁antagonism could be in concert with S1P receptor activity, or beindependent of activity at any S1P receptor.

In addition, disclosed compounds cart be useful for inhibition of groupIVA cytosolic PLA₂ (cPLA₂). cPLA₂ catalyzes the release of eicosanoicacids (e.g., arachidonic acid). The eicosanoic acids are transformed topro-inflammatory eicosanoids such as prostaglandins and leukotrienes.Thus, disclosed compounds may be useful as anti-inflammatory agents.This inhibition could be in concert with S1P receptor activity, or beindependent of activity at any S1P receptor.

In addition, disclosed compounds may be useful for inhibition of themultiple substrate lipid kinase (MuLK). MuLK is highly expressed in manyhuman tumor cells and thus its inhibition might slow the growth orspread of tumors.

Pharmaceutical compositions can include the compounds of formula I. Moreparticularly, such compounds can be formulated as pharmaceuticalcompositions using standard pharmaceutically acceptable carriers,fillers, solubilizing agents and stabilizers known to those skilled inthe art. For example, a pharmaceutical composition including a compoundof formula I, or a salt, analog, derivative, or modification thereof, asdescribed herein, is used to administer the appropriate compound to asubject.

The compounds of formula I are useful for treating a disease or disorderincluding administering to a subject in need thereof of atherapeutically acceptable amount of a compound of formula I, or apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, and a pharmaceutically-acceptable carrier.

The disclosed compounds and method are directed to sphingosine1-phosphate (S1P) analogs that have activity as receptor agonists orreceptor antagonists at one or more S1P receptors, specifically theS1P₁, S1P₄ or S1P₅ receptor types. The disclosed compounds and methodinclude both compounds that have a phosphate moiety as well as compoundswith hydrolysis-resistant phosphate surrogates such as phosphonates,alpha-substituted phosphonates (particularly where the alphasubstitution is a halogen), or phosphothionates.

In cases where compounds of formula I are sufficiently basic or acidicto form stable nontoxic acid or base salts, preparation andadministration of the compounds as pharmaceutically acceptable salts maybe appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also beformed, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Pharmaceutically-acceptable base addition salts can be prepared frominorganic and organic bases. Salts from inorganic bases, include but arenot limited to, sodium, potassium, lithium, ammonium, calcium ormagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary or tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, or mixed di- andtri-amines where at least two of the substituents on the amine aredifferent and are alkyl, substituted alkyl, alkenyl, substitutedalkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl, or heterocyclic and the like. Alsoincluded are amines where the two or three substituents, together withthe amino nitrogen, form a heterocyclic or heteroaryl group.Non-limiting examples of amines include, isopropylamine, trimethylamine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine,histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines,piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like.It should also be understood that other carboxylic acid derivativeswould be useful, for example, carboxylic acid amides, includingcarboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and thelike.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, e.g., orally or patenterally, as eyedrops, byintravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibietablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, or wafers, and the like. Such compositions and preparationsshould contain at least about 0.1% of active compound. The percentage ofthe compositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin: excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl or propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

Exemplary pharmaceutical dosage forms for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, or nontoxicglyceryl esters, and mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, or thimerosal, and the like. In many cases, it will be preferableto include isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, e.g., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Exemplary solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts oresters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508), each of which is incorporated by reference inits entirety.

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949, which is incorporated by reference in its entirety.

Generally, the concentration of the compound(s) of formula I in a liquidcomposition, such as a lotion, will be from about 0.1 to about 25 weightpercent, preferably from about 0.5-10 weight percent. The concentrationin a semi-solid or solid composition such as a gel or a powder will beabout 0.1-5 wt-%, preferably about 0.5-2.5 weight percent based on thetotal weight of the composition.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician. In general, however, a dose will be in the range of fromabout 0.1 to about 10 mg/kg of body weight per day.

The compound is conveniently administered in unit dosage form; forexample, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredientper unit dosage form. In some embodiments, a dose of 5 mg/kg or less issuitable.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose, ordivided doses administered at appropriate intervals, for example, astwo, three, four, or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The disclosed method includes a kit comprising a compound of formula Iand instructional material which describes administering the compound ora composition comprising the compound to a cell or a subject. Thisshould be construed to include other embodiments of kits that are knownto those skilled in the art, such as a kit comprising a (preferablysterile) solvent for dissolving or suspending the compound orcomposition prior to administering the compound or composition to a cellor a subject. Preferably, the subject is a human.

Compounds can have an EC₅₀ of between 5 nM and 3 μM when acting asselective agonists for S1P₁ receptors. While the EC₅₀ of certaincompounds acting as agonists to S1P₁ and S1P₃ receptors can be greaterthan 5000 nM, these same compounds can have an EC₅₀ of 0.2 nM-700 nMwhen acting as selective antagonists for S1P₅ receptors and 50 nM-3 μMwhen acting as selective antagonists for S1P₄ receptors.

In accordance with the disclosed compounds and methods, as describedabove or as discussed in the Examples below, there can be employedconventional chemical, cellular, histochemical, biochemical, molecularbiology, microbiology, and in vivo techniques which are known to thoseof skill in the art. Such techniques are explained fully in theliterature.

The following working examples are provided for the purpose ofillustration only, and are not to be construed as limiting in any waythe remainder of the disclosure. Therefore, the examples should beconstrued to encompass any and all variations which become evident as aresult of the teaching provided herein.

EXAMPLES Example 1 cis-4-tert-butylcyclohexyl methanesulfonate

Cis-4-t-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved indichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2mmol, 1.1 eq.) was added to the mixture slowly at 0° C. Thentriethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture andthe mixture stirred at room temperature for 3 h. The mixture wasextracted with dichloromethane and the organic layer was concentrated togive product as a white power (8.0 g, yield: 90%). The product was usedto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1.28 (m, 7H),0.84 (s, 9H).

Example 2 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene

6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.)was dissolved in a mixture of t-butanol/2-butanone (4 mL/2 mL). Thencesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was added to the mixture andthe mixture was stirred at 110° C. for 10 min. Thentrans-4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1eq.) was added to the mixture. The suspension was stirred at 110° C.under a nitrogen atmosphere for 15 h. The reaction mixture was extractedwith ethyl acetate and the organic layer was purified by silica gelcolumn chromatography using petroleum ether as eluent to give2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene as a slightyellow solid (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H),7.15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m,2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H).

Example 3 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde

2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere.Then the mixture was cooled down to −78° C. and a solution of n-BuLi inTHF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixturedropwise. The mixture was stirred at −78° C. for 15 min. Then DMF (2.4mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at −78° C.for 1 h. When the reaction completed, 1 M HCl was added to adjust the pHto 6. The mixture was extracted with EtOAc and the organic layer wasconcentrated and purified by silica gel chromatography using petroleumether/ethyl acetate (10/1) as eluent to give6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde as a white solid(1.16 g, 60%). EDI-MS: 311.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s,1H), 8.24 (s, 1H), 7.92-7.87 (m, 2M), 7.77 (d, 1M), 7.22-7.19 (m, 2H),4.42-4.30 (m, 1H), 2.30-2.28 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.11 (m,5H), 0.82 (s, 9H).

Example 4 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene(Alternate Synthesis)

To a solution of 6-bromonaphthalen-2-ol (100.0 g, 450.1 mmol),triphenylphosphine (230 g, 877.8 mmol, 2.0 eq) andcis-4-t-butylcyclohexanol (105.4 g, 675.7 mmol; 1.5 eq) in toluene (1.5L), was added dropwise diisopropyl azodicarboxylate (170 g, 850.0 mmol,2.0 eq) at 0° C. The addition took ˜2 hrs and the resulting mixture waswarmed to 26-30° C. After 24 hrs, thin layer chromatography showed nearcomplete consumption of 6-bromonaphthalen-2-ol. The mixture was thencooled to 5° C. and stirred at that temperature for 2 hrs, over whichsolids precipitated and were filtered. The filtrate was concentrated tonear dryness to afford an oil, which was taken up in 200 ml methylenechloride and purified by silica gel chromatography with 100% petroleumether. After concentration, 127 g product was obtained as a white solid(yield: 79.1%). EDI-MS: 361.1 (M+H)⁺.

Example 5 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-iodonaphthalene

A solution of 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene(160.0 g, 444.4 mmol) in methylene chloride (2.5 L) was purged under anatmosphere of argon. N-iodosuccinimide (202.1 g, 888.8 mmol) andzirconium tetrachloride (20.4 g, 88.9 mmol) was added and the reactionwas stirred at room temperature under an atmosphere of argon. Thereaction was monitored by ¹H NMR and showed complete conversion toproduct after 30 minutes. The mixture was then concentrated underreduced pressure to give ˜250 g crude as a brown solid. The crudematerial was purified by silica gel chromatography with hexanes to give200 g of desired product as a brown solid (yield: 92.6%). EDI-MS: 487.1(M+H)⁺.

Example 66-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene

A solution of6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-iodonaphthalene (210.0 g,433 mmol), hexamethylphosphoramide (386.4 g, 2.16 mol; 5 eq) inN,N-dimethylformamide (2.0 L) was degassed by stirring under vacuum andreplacing the vacuum with argon (4 times). To this mixture was addedcopper(I) iodide (140.0 g, 735 mmol; 1.7 eq) and methylfluorosulphonyldifluoroacetate (415 g, 2.16 mol; 5 eq). The reactionmixture was warmed to 80° C. under an atmosphere of argon. Afterstirring for 6 hrs, thin layer chromatography showed complete conversionto product. Saturated NaHCO₃ solution was added to adjust the final pHto 9˜10 followed by adding EtOAc (3.5 L). The mixture was extracted withEtOAc (2.5 L×3), and washed with brine (1.0 L×4), then dried over Na₂SO₄(500 g). The solvent was removed under reduced pressure to give crude195 g as a sticky off white solid with purity of >90%, which waspurified by silica gel chromatography with 0-30% EtOAc in hexanes togive the final product (156 g, 84.3%). EDI-MS: 430.0 (M+H)⁺.

Example 7 tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate

3-(Tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv)was dissolved in DCM (100 mL). Then phenylsulfonamide (15.1 mmol, 0.7equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol,0.15 equiv) were added to the mixture and stirred for 2 h at roomtemperature. The reaction mixture was cooled down to 0° C., ice water(100 mL) was added. The mixture was stirred for 15 min, separated andthe water layer was extracted twice with dichloromethane. The combinedorganic layer was washed by 5% HCl, brine, dried over Na₂SO₄,concentrated to give tert-butyl3-oxo-3-(phenylsulfonamido)propylcarbamate 5.3 g, gray oil, 100%.EDI-MS: 329.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ: 9.52˜9.43 (brs, 1H),8.02˜7.96 (m, 2H), 7.61-7.55 (m, 1H), 7.50-7.45 (m, 2H), 5.02-4.93 (m,1H), 3.30-3.24 (m, 2H), 2.48˜2.41 (m, 2H), 1.34 (s, 9H).

Example 8 3-amino-N-(phenylsulfonyl)propanamide

Tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate (3.6 g, 15.1 mmol)was dissolved in dichloromethane (60 mL). Then CF₃COOH (1.1 mL, 0.3mmol, 20 equiv ) was added to the mixture at 0° C. and stared for 2 h at0° C. The reaction mixture was concentrated and purified by flashchromatography to give 3-amino-N-(phenylsulfonyl)propanamide as a whitesolid (1.4 g, 40%). EDI-MS: 229.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ:7.79˜7.71 (m, 2H), 7.70˜7.43 (brs, 3H), 7.42˜7.34 (m, 3H), 2.83 (t, 2H),2.24 (t, 2H).

Example 93-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide

6-(Trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol,1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide (1.19 mmol, 1.5equiv) were dissolved in anhydrous ethanol. The mixture was stirred at80° C. for 1 h. Then NaBH₃CN (110 mg, 1.74 mmol, 2 equiv) was added tothe mixture and stirred at 80° C. for 16 h. The organic layer wasconcentrated and purified by preparative thin layer chromatography(mobile phase was methanol:dichloromethane 1:10) to give3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamideas a white solid. 284 mg, white solid, 62%. ESI-MS: 523.0 (M+H)⁺. HPLC:99.42%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.91 (s, 1H), 7.85˜7.82 (m, 2H),7.74˜7.72 (m, 2H), 7.53˜7.51 (m, 1h), 7.41˜7.35(m, 4H), 7.20˜7.15 (m,1H), 4.45˜4.40 (m, 1H), 4.23 (s, 2H), 2.99 (t, 2H), 2.33 (t, 2H),2.28˜2.16 (m, 2H), 1.89˜1.78 (m, 2H), 1.41˜1.31 (m, 2H), 1.27˜1.17 (m,2H), 1.13˜1.06 (m, 1H), 0.89 (s, 9H).

Example 103-((6-(trans-4-tert-butylcyclohexyoxy)-5-(trifluoromethyl)naphthalen-2-ylmethylamino)-N-(phenylsulfonyl)propanamide

6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde(300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(phenylsulfonyl)propanamide(1.19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixturewas stirred at 80° C. for 1 h. Then NaBH₃CN (110 mg, 1.74 mmol, 2 equiv)was added to the mixture and stirred at 80° C. for 16 h. The organiclayer was concentrated and purified by preparative thin layerchromatography (mobile phase was methanol:dichloromethane 1:10) to give3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamideas a white solid. 120 mg, white solid, 53%, ESI-MS: 591.0 (M+H)⁺. HPLC:98.05%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.22˜8.13 (m, 1H), 8.11˜8.04 (m,2H), 7.79˜7.63 (m, 4H), 7.45˜7.30(m, 3H), 4.63˜4.49(m, 1H), 4.27 (s,2H), 2.99 (t, 2H), 2.32 (t, 2H), 2.19˜2.07 (m, 2H), 1.85˜1.74 (m, 2H),1.45˜1.30 (m, 2H), 125˜1.12 (m, 2H), 1.10˜0.97 (m, 1H), 0.86 (s, 9H).

Example 11 methyl2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate

A mixture of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (155mg, 0.5 mmol), methyl 2-aminopropanoate (103 mg, 1.0 mmol, 2.0 equiv)and AcOH (59 mg, 1.0 mmol, 2.0 equiv) in anhydrous dichloroethane (20mL) was refluxed for 30 min, cooled to 23° C., NaBH₃CN (60 mg, 1.0 mmol,2.0 equiv) was added, the resulted mixture was refluxed for 1 h. Thereaction mixture was concentrated in vacuum and the residue was purifiedby chromatography with silica gel (dichloromethane:methanol 20:1) togive methyl2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoateas a white solid (277 mg, yield: 70%). ESI-MS: 398.1 (M+H)⁺. HPLC:96.09%. ¹H NMR (400 MHz, CD₃OD) δ: 7.83 (s, 1H), 7.79 (d, 1H), 7.74 (d,1H), 7.43 (dd, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 4.28-4.33 (m, 3H), 4.13(q, 1H), 3.80 (s, 3H), 2.21 (d, 2H), 1.85 (d, 2H), 1.56 (d, 3H),1.31-1.37 (m, 2H), 1.17-1.24 (m, 2H), 1.05-1.11 (m, 1H), 0.85 (s, 9H).

Example 122-((6-(trans-4-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid

To a solution of methyl2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate(100 mg, 0.25 mmol) in ethanol (10 mL) was added aqueous NaOH (3 mL,20%, 5.0 eq.) and refluxed for 1 hr. Then the reaction was cooled to 0°C., the pH of the solution was adjusted to 6 with 1 M HCl, concentratedand the residue was dissolved in dichloromethane, washed with water,dried and concentrated to give2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid as a white solid (70 mg, yield: 75%). ESI-MS: 384.1 (M+H)⁺. HPLC:97.18%. ¹H NMR (400 MHz, CD₃OD) δ: 7.88 (s, 1H), 7.83 (d, 1H), 7.73 (d,1H), 7.49 (dd, 1H), 7.26 (d, 1H), 7.15 (dd, 1H), 4.29-4.38 (m, 3H), 4.04(q, 1H), 2.25 (d, 2H), 1.90 (d, 2H), 1.60 (d, 3H), 1.36-1.44 (m, 2H),1.21-1.31 (m, 2H), 1.09-1.15 (m, 1H), 0.89 (s, 9H).

Example 13 ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate

6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (30 mg, 0.097mmol), ethyl 3-aminobutanoate (CAS no. 5303-65-1) (19 mg, 0.145 mmol),and acetic acid (17 mg, 0.291 mmol) were dissolved in dichloroethane (2mL). The mixture was stirred at r.t. for 10 min under nitrogenatmosphere. Then NaBH(OAc)₃ (41 mg, 0.194 mmol) was added to the mixtureand the mixture was stirred at r.t. for 15 h. Then saturated NaHCO₃ wasadded to the mixture to adjust the pH to 8. The mixture was extractedwith ethyl acetate and the organic layer was purified by silica gelcolumn chromatography using dichloromethane:methanol 10:1 to giveproduct ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate(40 mg, 88%) as a slight yellow solid. ESI-MS: 426.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.70-7.65 (m, 3H), 7.41 (d, 1H), 7.13-7.09 (m, 2H),4.28-4.23 (m, 1H), 4.12 (q, 2H), 3.98-3.88 (m, 2H), 3.22-3.18 (m, 1H),2.53-2.42 (m, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m,2H), 1.26-1.09 (m, 9H), 0.90 (s, 9H).

Example 143-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 9 mg, slight yellow oil, yield: 27%. ESI-MS: 398.1 (M+H)⁺. HPLC:91.26%. ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.61 (m, 3H), 7.45 (d, 1H), 7.07(t, 2H), 4.20-4.17 (m, 2H), 3.98-3.95 (m, 1H), 3.18-3.16 (m, 1H),2.43-2.42 (m, 2H), 2.24-2.18 (m, 2H), 1.87-1.84 (m, 2H), 1.34-1.17 (m,8H), 0.91 (s, 9H).

Example 15 ethyl2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)acetate

A mixture of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (155mg, 0.5 mmol) and ethyl 2-(methylamino)acetate (117 mg, 1.0 mmol, 2.0equiv) in anhydrous ethanol (20 mL) was refluxed for 2 hr and evaporatedin vacuum to dryness. Anhydrous EtOH was added and refluxed for 1 hr,and then the mixture was cooled to 23° C. NaBH₃CN (60 mg, 1.0 mmol, 2.0equiv) was added. The resulted mixture was refluxed for 1 h. Thereaction mixture was concentrated in vacuum and the residue was purifiedby chromatography with silica gel (dichloromethane:methanol 20:1) togive product ethyl2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)acetateas a white solid (82 mg, yield: 40%). ESI-MS: 411.3 (M+H)⁺. HPLC:98.93%. ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.67 (m, 3H), 7.00 (d, 1H),7.14-7.13 (m, 2H), 4.30-4.28 (m, 1H), 4.18 (q, 2H), 3.82 (s, 3H), 3.30(s, 2H), 2.45 (s, 3H), 2.99-2.27 (m, 2H), 1.91-1.88 (m, 2H), 1.46-1.42(m, 2H), 1.29-1.22 (m, 3H), 0.90 (s, 9H).

Example 162-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)aceticacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 14 mg, gray solid, yield: 75%. ESI-MS: 383.3 (M+H)⁺. HPLC: 95.11%,¹H NMR (400 MHz, CD₃OD) δ 7.98 (s, 1H), 7.91-7.85 (m, 2H), 7.59-7.57 (m,1H), 7.33 (s, 1H), 7.22 (d, 1H), 4.55 (s, 2H), 4.42-4.40 (m, 1H), 4.10(s, 2H), 2.95 (s, 3H), 2.32-2.29 (m, 2H), 1.96-1.93 (m, 2H), 1.47-1.41(m, 2H), 1.35-1.25 (m, 3H), 0.95 (s, 9H).

Example 17 ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate

The title compound was synthesized as described for ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate.730 mg, white solid, 40.9%, ESI-MS: 412.3 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ: 7.75 (s, 1H), 7.72-7.67 (m, 2H), 7.50 (dd, 1H), 7.12-7.10 (m,1H), 7.07 (d, 1H), 4.20 (m, 1H), 4.11 (q, 2H), 4.01 (s, 2H), 3.05 (t,2H), 2.81 (t, 2H), 2.22-2.20 (m, 2H), 1.87-1.84 (m, 2H), 1.41-1.38 (m,2H), 1.22 (t, 3H), 1.17-1.07 (m, 3H), 0.89 (s, 9H).

Example 183-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 593 mg, beige solid, yield: 87.2%, ESI-MS: 384.1 (M+H)⁺. HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 7.84(s, 1H), 7.81-7.75 (m, 2H), 7.45(dd, 1H), 7.22 (d, 1H), 7.14 (dd, 1H), 4.34-4.32 (m, 1H), 4.28 (s, 2H),3.17 (t, 2H), 2.49 (t, 2H), 2.28-2.25 (m, 2H), 1.92-1.88 (m, 2H),1.43-1.40 (m, 2H), 1.25-1.22 (m, 2H), 1.13-1.10 (m, 1H), 0.90 (s, 9H).

Example 19 ethyl3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)propanoate

The title compound was synthesized as described for methyl2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoate.

100 mg, white solid, yield: 70%, ESI-MS: 426.3 (M+H)⁺. HPLC: 90.71%, 1HNMR (400 MHz, CD3OD) S; 7.73-7.76 (m, 3H), 7.43 (dd, 1H), 7.24 (d, 1H),7.12 (dd, 1H), 4.31-4.37 (m, 1H), 4.12-4.17 (m, 2H), 3.87 (s, 2H), 2.96(t, 2H), 2.66 (t, 2H), 2.40 (s, 3H), 2.28 (d, 2H), 1.91 (d, 2H),1.39-1.46 (m, 2H), 1.22-1.31 (m, 5H), 1.10- 1.17 (m, 1H), 0.93 (s, 9H).

Example 203-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)propanoicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 70 mg, white solid, yield: 75%. ESI-MS: 398.3 (M+H)⁺. HPLC:94.61%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.97 (s, 1H), 7.87 (d, 1H), 7.83(d, 1H), 7.62 (d, 1H), 7.43 (d, 1H), 7.19 (dd, 1H), 4.39-4.44 (m, 3H),3.27 (br, 2H), 2.85 (t, 2H), 2.67 (s, 3H), 2.21 (d, 2H), 1.82 (d, 2H),1.32-1.38 (m, 2H), 1.18-1.27 (m, 2H), 1.03-1.08 (m, 1H), 0.88 (s, 9H).

Example 20 methyl1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The title compound was synthesized as described for methyl2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate.150 mg, white solid, yield: 61%. ESI-MS: 410.3 (M+H)⁺. HPLC: 92.03%. ¹HNMR (400 MHz, CD₃OD) δ: 7.88 (s, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 7.44(dd, 1H), 7.28 (d, 1H), 7.17 (dd, 1H), 4.51 (s, 2H), 4.32-4.39 (m, 5H),3.72-3.77 (m, 4H), 2.26 (d, 2H), 1.90 (d, 2H), 1.36-1.47 (m, 2H),1.24-1.31 (m, 2H), 1.11-1.17 (m, 1H), 0.91 (s, 9H).

Example 211-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 70 mg, white solid, yield: 70%. ESI-MS: 396.3 (M+H)⁺. HPLC:90.04%, ¹H NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.86 (d, 1H), 7.83 (d,1H), 7.47 (dd, 1H), 7.30 (s, 1H), 7.19 (dd, 1H), 4.53 (s, 2H), 4.30-4.51(m, 5H), 3.66-3.70 (m, 1H), 2.29 (d, 2H), 1.93 (d, 2H), 1.39-1.48 (m,2H), 1.24-1.33 (m, 2H), 1.14-1.17 (m, 1H), 0.93 (s, 9H).

Example 22 methyl1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylate

The title compound was synthesized as described for ethyl2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)acetate.150 mg, white solid, yield: 55%, ESI-MS: 423.3 (M+H)⁺. HPLC: 98.59%, ¹HNMR (400 MHz, CDCl₃) δ 7.69-7.67 (m, 3H), 7.42 (d, 1H), 7.12 (t, 2H),4.27-4.25 (m, 1H), 3.87 (s, 2H), 3.69 (s, 3H), 3.12-3.06 (m, 2H),2.88-2.84 (m, 2H), 2.73-2.70 (m, 1H), 2.28-2.25 (m, 2H), 2.18-2.16 (m,2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.25-1.12 (m, 3H), 0.89 (s,9H).

Example 231-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 80 mg, white solid, yield: 55%, ESI-MS: 409.3 (M+H)⁺. HPLC:93.50%. 1H NMR (400 MHz, CD₃OD) δ 7.95 (s, 1H), 7.83 (dd, 2H), 7.55 (d,1H), 7.28 (s, 1H), 7.18 (d, 1H), 4.55-4.47 (m, 2H), 4.41-4.34 (m, 1H)3.63-3.37 (m, 2H), 3.32 (s, 2H), 3.28-3.20 (m, 1H), 2.42-2.27 (m, 4H),1.94-1.90 (m, 2H), 1.48-1.38 (m, 2H), 1.33-1.23 (m, 2H), 1.23-1.14 (m,1H), 0.89 (s, 9H).

Example 24 ethyl1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate

The title compound was synthesized as described for ethyl2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)acetate.100 mg, white solid, yield: 46%. ESI-MS: 451.3 (M+H)⁺. HPLC: 92.64%. ¹HNMR (400 MHz, CDCl₃) δ 7.75-7.72 (m, 3H), 7.48 (dd, 1H), 7.17 (d, 2H),4.30-4.28 (m, 1H), 4.16 (q, 2H), 3.96 (s, 2H), 3.09-3.08 (m, 2H),2.53-2.51 (m, 3H), 2.29-2.26 (m, 2H), 2.10-2.03 (m, 4H), 1.91-1.88 (m,2H), 1.43-1.43 (m, 2H), 1.18-1.13 (m, 6H), 0.88 (s, 9H).

Example 251-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylicacid

Synthesis was performed as described for2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoicacid. 70 mg, white solid, yield: 87%. ESI-MS: 423.3 (M+H)⁺. HPLC:94.25%. ¹H NMR (400 MHz, CD₃OD) δ 7.90 (s, 1H), 7.86 (dd, 2H), 7.56 (d,1H), 7.32 (s, 1H), 7.20 (dd, 1H), 4.46 (s, 2H), 4.42-4.39 (m, 1H),3.61-3.59 (m, 2H), 3.19-3.15 (m, 2H), 2.72-2.60 (m, 1H), 2.31-2.27 (m,4H), 1.95-1.92 (m, 4H), 1.46-1.42 (m, 2H), 1.34-1.27(m, 3H), 0.93 (s,9H).

Example 266-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde

To a solution of6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene(1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL, 2.5M in THF,3.0 equiv) dropwise at −78° C. in 30 min, then DMF (840 mg, 11.5 mmol,5.0 equiv) was added slowly at −78° C. The reaction mixture was stirredat −78° C. for 1.5 h. Then saturated NH₄Cl solution was added to themixture to quench the reaction. The mixture was extracted with EtOAc andpurified by silica gel chromatography (petroleum ether:ethyl acetate10:1) to give product6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehydeas a yellow solid (608 mg, 70%) ESI-MS: 379.2 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ: 10.13 (s, 1H), 8.28 (d, 2H), 8.08 (d, 1H), 7.98-8.01 (dd, 1H),7.41 (d, 1H), 4.39 (m, 1H), 2.21 (d, 2H), 1.90 (d, 2H), 1.49-1.58 (q,2H), 1.10-1.17 (m, 3H), 0.86 (s, 9H)

Example 27 methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate

A mixture of6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde(300 mg, 0.8 mmol) and methyl azetidine-3-carboxylate (184 mg, 1.6 mmol,2.0 equiv) in anhydrous ethanol (20 mL) was refluxed for 2 h. Then thesolvent was removed in vacuo, fresh ethanol and NaBH₃CN (150 mg, 2.4mmol, 3.0 equiv) was added, the resulting mixture was refluxed for 1 h.The reaction mixture was concentrated and the residue was purified bychromatography with silica gel (dichloromethane:methanol 20:1) to giveproduct methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylateas a white solid (150 mg, yield: 40%). ESI-MS: 477.3 (M+H)⁺. HPLC:85.67% ¹H NMR (400 MHz, CD₃OD) δ: 8.09 (dd, 1H), 8.01 (d, 1H), 7.56 (s,1H), 7.46-7.51 (m, 2H), 4.42 (m, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.57(t, 2H), 3.45 (t, 2H), 3.35-3.39 (m, 1H), 2.18 (d, 2H), 1.88 (d, 2H),1.43-1.52 (q, 2H), 1.09-1.22 (m, 3H), 0.89 (s, 9H)

Example 281-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

To a solution of methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate(100 mg, 0.25 mmol) in ethanol (10 mL) was added aqueous NaOH (3 mL,20%) and refluxed for 1 h. Then the reaction was cooled to 0° C., the pHof the solution was adjusted to 6 with 1 M HCl, and concentrated. Theresidue was dissolved in dichloromethane, washed with water, dried andconcentrated to give1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid as a white solid (70 mg, yield: 70%). ESI-MS: 464.2 (M+H)⁺. HPLC:98.64% ¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (d, 2H), 8.08 (d, 2H), 7.72 (d,1H), 7.67 (d, 1H), 4.60-4.58 (m, 1H), 4.51 (s, 2H), 4.21 (d, 4H),3.55-3.67 (m, 1H), 2.13 (d, 2H), 1.80 (d, 2H), 1.35-1.43 (q, 2H),1.03-1.22 (m, 3H), 0.86 (s, 9H).

Example 29 ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoate

Synthesis was performed as described for methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate.50 mg, white solid (yield: 20%). ESI-MS: 480.3 (M+H)⁺. HPLC: 89.20% ¹HNMR (400 MHz, DMSO-d₆) δ: 8.22 (d, 1H), 8.97 (d, 1H), 7.90 (s, 1H), 7.52(d, 1H), 7.33 (d, 1H), 4.30-4.28 (m, 1H), 4.14-4.20 (m, 4H), 3.17 (s,2H), 2.77 (s, 2H), 2.16 (d, 2H), 1.86 (d, 2H), 1.47-1.55 (q, 2H), 1.25(t, 3H), 1.09-1.13 (m, 3H), 0.87 (s, 9H).

Example 303-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoicacid

Synthesis was performed as described for1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 30 mg, white solid (yield: 70%). ESI-MS: 452.2 (M+H)⁺. HPLC:94.35% ¹H NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, 1H), 8.01 (d, 1H), 7.91 (s,1H), 7.62 (d, 2H), 4.54-4.52 (m, 1H), 3.93 (s, 2H), 2.79 (t, 2H), 2.36(t, 2H), 2.12(d, 2H), 1.79 (d, 2H), 1.35-1.41 (q, 2H), 1.03-1.22 (m,3H), 0.86 (s, 9H).

Example 31 methyl 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoate

A mixture of cis-4-tert-butylcyclohexanal (927 mg, 0.00593 mol),6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494mol) and triphenylphosphine (1560 mg, 0.00593 mol) in toluene (10 mL,0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6hours. The mixture was taken up into dichloromethane and was purifiedvia column chromatography with ethyl acetate:hexane (0:100 to 40:60) togive methyl 6-(trans-4-tert-butytcyclohexyloxy)-2-naphthoate as a whitesolid (0.95 g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.01 (dd,J=8.7, 1.7 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.17(m, 2H), 4.34 (m, 1H), 3.97 (s, 3H), 2.30 (m, 2H), 1.92 (m, 2H),1.52-1.14 (m, 5H), 0.91 (s, 9H).

Example 32 (6-trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanol

Methyl 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoate (950 mg, 0.0028mol) was dissolved in tetrahydrofuran (20 mL, 0.2 mol) and 1.0 M lithiumtetrahydroaluminate in tetrahydrofuran (8.4 mL, 0.0084 mol) was thenadded at 0° C. After stirring at room temperature for 2 hours, ethylacetate and Rochele's salt was added and the mixture was then stirred atroom temperature for 1 hour. After extraction with ethyl acetatefollowed by concentration under reduced pressure, the product(6-trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methanol was obtainedas a white solid (770 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (m, 2H),7.45 (d, J=10.1 Hz, 1H), 7.15 (m, 3H), 4.82 (AB, J=16.1, 16.1 Hz, 2H),4.28 (m, 1H), 2.27-2.31 (m, 2H), 1.89-1.92 (m, 2H), 1.11-1.50 (m, 5H),0.91 (s, 9H).

Example 33 6-(trans-4-tert-Butylcyclohexyloxy)-2-naphthaldehyde

To (6-trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanol (150 mg,0.480 mmol) in methylene chloride (5 mL, 80 mmol) was added theDess-Martin periodinane (0.285 g, 0.672 mmol) and the mixture wasstirred at room temperature for 1 hour. The crude reaction mixture wasthen passed through a silica gel plug and the filtrate was thenconcentrated under reduced pressure to give the product as a white solid(0.150 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.25 (s, 1H),7.92-7.87 (m, 2H), 7.78 (d, J=8.5Hz, 1H), 7.23-7.19 (m, 2H), 4.38-4.30(m, 1H), 2.31-2.29 (m, 2H), 1.94-1.91 (m, 2H), 1.54-1.11 (m, 5H), 0.92(s, 9H).

Example 343-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-difluoropropanoicacid

A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(150 mg, 0.483 mmol) and 3-amino-2,2-difluoro-propionic acid (60.4 mg,0.483 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h.The yellow solution was then cooled to room temperature and sodiumcyanoborohydride (36.4 mg, 0.580 mmol) was added to the stirringsolution. The resulting mixture was heated to reflux for 1 h. Aftercooling to room temperature, citric acid was added, and the solventremoved under vacuum. The resulting solid was suspended in water andcollected via filtration. The filtrate was washed thoroughly with water(4×), ether (3×), and hexane (3×). The resulting solid was dried on thefilter to give the title compound as a white solid (128.8 mg, 64%). ¹HNMR (400 MHz, CDCl₃) δ: 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.82 (d,J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H),7.19 (dd, J=9.0, 2.4 Hz, 1H), 4.45 (s, 2H), 4.40 (m, 1H), 3.61 (t,J=13.8 Hz, 2H), 2.28-2.31 (m, 2H), 1.92-1.95 (m, 2H), 1.49-1.14 (m, 5H),0.94 (s, 9H).

Example 35 methyl 6-(spiro[5.5]undecan-3-yloxy)-2-naphthoate

A mixture of spiro[5,5]undecan-3-ol (0.999 g, 0.00593 mol),6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1mol) was heated to reflux. Diisopropyl azodicarboxylate (1.17 mL,0.00593 mol) was then added dropwise and the resulting mixture wasrefluxed for 6 hours. The mixture was then diluted with dichloromethaneand subjected to chromatographic purification with ethyl acetate:hexane(0:100 to 40:60) to give methyl6-(spiro[5.5]undecan-3-yloxy)-2-naphthoate as a white solid. (1.09 g,62%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.01 (dd, J=8.7, 1.7 Hz,1H), 7.84 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (m, 2H), 4.45(m, 1H), 3.97 (s, 3H), 1.93-1.28 (m, 18H).

Example 36 (6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methanol

To a solution of 6-(Spiro[5.5]undec-3-yloxy)-naphthalene-2-carboxylicacid methyl ester (0.374 g, 0.00106 mol) in tetrahydrofuran (10 mL, 0.1mol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran(3.18 mL, 0.00318 mol) at 0° C. The reaction was then allowed to warm toroom temperature while stirring for 2 h, Rochele's salt was then addedand stirred the resulting mixture was stirred at room temperature for 1h. After extraction with ethyl acetate, and solvent removal undervacuum, (6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methanol wasobtained as a white solid (0.28 g, 83%). ESI-MS: 307.5 (M+H)⁺. 100%). ¹HNMR (400 MHz, CDCl₃) δ 7.74-7.70 (m, 3H), 7.44 (d, J=10.0 Hz, 1H), 7.16(m, 2H), 4.81 (s, 2H), 4.40 (m, 1H), 1.94-1.26 (m, 18H).

Example 37 6-(spiro[5.5]undecan-3-yloxy)-2-naphthaldehyde

To [6-(Spiro[5.5]undec-3-yloxy)-naphthalen-2-yl]-methanol (150 mg, 0.46mmol) in methylene chloride (5 mL, 80 mmol) was added Dess-Martinperiodinane (0.274 g, 0.647 mmol) and the resulting solution was stirredat room temperature for 1 hour. The crude reaction was then passedthrough a silica gel plug, the filtrate was removed under vacuum to give6-(spiro[5.5]undecan-3-yloxy)-2-naphthaldehyde as a colorless solid.(0.150 g, 100%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.25 (s, 1H),7.92-7.89 (m, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.24-7.19 (m, 2H), 4.48 (m,1H), 1.96-1.29 (m, 18H).

Example 382,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoicacid

A solution of 6-(spiro[5,5]undec-3-yloxy)-naphthalen-2-carbaldehyde (150mg, 0.46 mmol) and 3-amino-2,2-difluoro-propionic acid (58.2 mg, 0.465mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. Theyellow solution was then cooled to room temperature and sodiumcyanoborohydride (35.1 mg, 0.558 mmol) was added portionwise. Theresulting mixture was heated to reflux for 1 h. The reaction was thencooled to room temperature, and citric acid was added. The solution wasstirred for several minutes and the solvent removed under vacuum. Theresulting solid was suspended in water and filtered, and the collectedsolid was washed thoroughly with water (4×), ether (5×), and hexane (5×)to give (82.1 mg, 41%) of2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoicacid. ¹H NMR (400 MHz, CDCl₃) δ: 7.93 (s, 1H), 7.86 (d, J=8.5Hz, 1H),7.83 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz,1H), 7.22 (dd, J=9.0, 2.4 Hz, 1H), 4.52 (m, 1H), 4.45 (s, 2H), 3.60 (t,J=15.9 Hz, 2H), 1.76-1.35 (m, 18H).

Example 39 (R)-ethyl1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylate

6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (500 mg, 2mmol) was combined with (R)-piperidine-3-carboxylic acid ethyl ester(0.51 g, 3.2 mmol) in methanol (10 mL, 200 mmol) and acetic acid (9.2μL, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmol) was thenadded and the reaction was stirred overnight at room temperature. Thereaction was then quenched with water and extracted three times withethyl acetate. Organics were combined and dried over MgSO₄. Solids wereremoved via filtration and 10 g of silica gel was added. All solvent wasthen removed and the resulting silica gel was loaded onto a 24 g columnand the product was eluted using a gradient of 0-60% ethylacetate/hexanes and then dried under vacuum to give the title compoundas a colorless oil. EDI-MS: 438.1 (M+H)⁺.

Example 40(R)-1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylicacid

(R)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylicacid ethyl ester (363.4 mg, 0.8046 mmol) was dissolved in ethanol (5 mL,80 mmol) then treated with 1 M aqueous sodium hydroxide (5 mL, 5 mmol).The mixture was stirred vigorously for 18 hours. pH was adjusted to 3-4with 3 N HCl and reaction was then extracted three times with ethylacetate. Organics were combined then dried over MgSO₄, filtered andconcentrated to dryness under reduced pressure. Ethyl ether was thenadded and a white precipitate formed which was removed via filtration togive a white solid that 86% pure by HPLC. The process was repeated twoadditional times to give the title compound as a white solid (156 mg,44%), EDI-MS: 424.2 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ=7.82 (s, 1 H),7.74-7.62 (m, 2 H), 7.42 (d, J=2.3, 1 H), 7.19 (d, J=2.3 Hz, 1 H), 7.08(d, J=2.5, 1 H), 4.43-4.34 (m, 1 H), 4.33-4.22 (m, 2 H), 2.71 (br. s., 1H), 2.16 (d, J=2.0 Hz, 2H), 1.88-167 (m, 4 H), 1.40-1.25 (m, 3 H),1.24-1.11 (m, 4 H), 1.10-0.95 (m, 5 H), 0.79 (s, 9 H)

Example 41 (S)-methyl1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylate

6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (503.27 mg,1.6212 mmol) was combined with in methanol (10 mL, 200 mmol) and aceticacid (9.2 μL, 0.16 mmol). Sodium cyanoborohydride (252.76 mg, 4.0221mmol) was then added and the reaction was stirred overnight at roomtemperature. The reaction was then quenched with water and extractedthree times with ethyl acetate. Organics were combined and dried overMgSO₄. Solids were removed via filtration and 7 g of silica gel wasadded. All solvent was then removed and the resulting silica was loadedonto a 24 g column and the product was eluted using a gradient of 0-60%ethyl acetate/hexanes and then dried under vacuum to give the titlecompound as a colorless oil (366 mg, 45%). EDI-MS: 438.3 (M+H)⁺.

Example 42(S)-1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-3-carboxylicacid

(S)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylicacid ethyl ester (151.23 mg, 0.33484 mmol) was dissolved in ethanol (5mL, 80 mmol) then treated with 1 M sodium hydroxide in water (5 mL, 5mmol). The mixture was stirred vigorously for 18 hours. pH was adjust to3-4 with 3 N HCl and reaction was then extracted three times with ethylacetate. Organics were combined then dried over MgSO₄, filtered andconcentrated to dryness under reduced pressure. Diethyl ether was thenadded and a white precipitate formed which was removed via filtration togive the title compound as a white solid (21 mg, 13%). EDI-MS: 424.1(M+H)⁺. ¹H NMR (400 MHz, MeOD) δ=7.82 (s, 1 H), 7.74-7.62 (m, 2 H). 7.44(d, J=2.3, 1 H), 7.19 (d, J=2.3 Hz, 1 H), 7.08 (d, J=2.5, 1 H),4.43-4.34 (m, 1 H), 4.33-4.22 (m, 2 H), 2.71 (br. s., 1 H), 2.16 (d,J=2.0 Hz, 2 H), 1.88-167 (m, 4 H), 1.40-1.25 (m, 3 H), 1.24-1.11 (m, 4H), 1.11-0.94 (m, 5 H), 0.80 (s, 9 H).

Example 434-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-butyricacid tert-butyl ester

A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in1,2-dichloroethane (1.5 mL) was treated with sodiumtriacetoxyborohydride (65 mg, 0.29 mmol). After stirring at roomtemperature over night, the mixture was diluted with dichloromethane andwashed with aqueous sodium bicarbonate. The organic phase was dried overMgSO₄, filtered and concentrated and residue was purified by silica gelcolumn eluted with ethyl acetate in hexane from 0 to 100% to givecolorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)⁺; ¹H NMR (400MHz, CDCl₃) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H),4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d,2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s,9H).

Example 444-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-butyricacid

A solution of4-{[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-butyricacid tert-butyl ester (33 mg, 0.073 mmol) in 4 M HCl in dioxane (1.50mL) was stirred at room temperature overnight to form a whiteprecipitate. The precipitate was filtered and washed with ether to giveproduct as the HCl salt (20 mg, yield: 63%). ESI-MS: 398.1 (M+H)⁺; (400MHz, CD₃OD) δ=7.90 (s, 1H), 7.84 (d, 1H), 7.81 (d, 1H), 7.49 (dd, 1H),7.28 (d, 1H), 7.17 (dd, 1H), (m, 2H), 4.37 (m, 1H), 4.33 (s, 2H), 3.15(t, 2H), 2.47 (t, 2H), 2.28 (t, 2H), 2.0 (m, 2H), 1.92 (d, 2H), 1.43 (q,2H), 1.27 (q, 2H), 1.13 (m, 1H), 0.92 (s, 9H).

Example 45{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-aceticacid ethyl ester

A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(90 mg, 0.29 mmol), glycine ethyl ester hydrochloride (162 mg, 1.16mmol), and triethylamine (0.16 mL, 1.16 mmol) in 1,2-dichloroethane (2mL) was treated with sodium triacetoxyborohydride (129 mg, 0.58 mmol).The mixture was stirred at room temperature overnight. The solution wasdiluted with dichloromethane and washed with aqueous sodium bicarbonate.The organic phase was dried over MgSO₄ and concentrated. The residue waspurified with a silica gel column eluted with ethyl acetate in hexanefrom 0 to 100% to give product (64 mg, yield: 55%). ESI-MS: 420.30(M+23)⁺; ¹H NMR (400 MHz, CDCl₃) δ=7.66-7.70 (m, 3H), 7.41 (dd, 1H),7.11-7.14 (m, 2H), 4.26 (m, 1H), 4.19 (q, 2H), 3.93 (s, 2H), 3.43 (s,2H), 2.28 (d, 4H), 1.89 (d, 2H), 1.44 (q, 2H), 1.27 (t, 3H), 1.09-1.20(m, 3H), 0.89 (s, 9H).

Example 46{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-aceticacid

To a solution of{[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-aceticacid ethyl ester (60 mg, 0.15 mmol) in methanol (1 mL) was added aqueouslithium hydroxide (4.2 M, 0.5 mL, 2 mmol) to form a white precipitate.The mixture slurry was stirred at room temperature for 3 hrs then at 50°C. for 2 hrs. The slurry was neutralized with 1 N HCl to pH 6 and thewhite precipitate was filtered and dried under vacuum to give whiteprecipitate (48 mg, yield: 86%). ESI-MS: 392.3 (M+23)⁺; ¹H NMR (400 MHz,DMSO) δ=7.77-7.82 (m, 3H), 7.48 (dd, 1H), 7.37 (d, 1H), 7.15 (dd, 1H),4.38 (m, 1H), 4.07 (s, 2H), 3.16 (s, 2H), 2.20 (d, 2H), 1.82 (d, 2H),1.35 (m, 2H), 1.10-1.25 (m, 3H), 0.89 (s, 9H).

Example 47(2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethyl)-phosphonicacid diethyl ester

To a solution of (2-amino-ethyl)-phosphonic acid diethyl ester oxalicacid salt (200 mg, 0.74 mmol) in 1,2-dichloroethane (3 mL) was added6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (343 mg, 1.1mmol). The mixture was stirred at room temperature for 1 hour, thensodium triacetoxyborohydride (329 mg, 1.5 mmol) was added. After beingstirred at room temperature overnight, the reaction mixture was quenchedwith water, stirred at room temperature for 30 min, then diluted withethyl acetate, and washed with aqueous NaHCO₃. The organic layer wasdried over MgSO₄ and purified with a silica gel column eluted with ethylacetate (100%), then eluted with methanol in dichloromethane from 0 to15% to give sticky oil (130 mg, yield: 25%). ESI-MS: 476.3 (M+H)⁺.

Example 48(2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethyl)phosphonicacid

To a solution of(2-{[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethyl)-phosphonicacid diethyl ester (65.00 mg, 0.14 mmol) in acetonitrile (1 mL) wasadded bromotrimethylsilane (1 mL, 7.58 mmol). The reaction was thenstirred at 50° C. overnight. After the solvent was concentrated, theresidue was purified with HPLC (acetonitrile-water, 15-85%) to givewhite precipitate (33 mg, yield: 58). ESI-MS: 420.2 (M+H)⁺; ¹H NMR (400MHz, DMSO) δ=7.81-7.91 (m, 3H), 7.51 (dd, 1H), 7.41 (d, 1H), 7.19 (dd,1H), 4.40 (m, 1H), 4.31 (s, 2H), 3.12 (m, 2H), 2.21 (d, 2H), 1.97 (m,2H), 1.82 (d, 2H), 1.36 (q, 2H), 1.22 (q, 2H), 1.08 (m, 1H), 0.88 (s,9H).

Example 49 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butylester

A mixture of 2,3-dihydro-1H-indol-5-ol (1.0 g, 7.8 mmol),di-tert-butyldicarbonate (4.0 g, 18 mmol), chloroform (20 mL) andsaturated sodium bicarbonate aq. (8 mL) was stirred at room temperatureover night. The organic phase was separated and washed twice with water,dried over MgSO₄, filtered and concentrated to give crude product. Thecrude material was treated with ether and filtered to give product (1.1g, yield: 60%). ESI-MS: 258.10 (M+23)⁺, ¹H NMR (400 MHz, DMSO) δ 9.00(s, 1H), 7.48 (ws, 1H), 6.61 (d, 1H), 6.51 (dd, 1H), 3.84 (t, 2H), 2.96(t, 2H), 1.48 (s, 9H).

Example 505-(trans-4-tert-Butyl-cyclohexyloxy)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester

A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butylester (0.6 g, 2.6 mmol) in tert-butyl alcohol (8 mL) and 2-butanone (4mL) was added cesium carbonate (2.5 g, 7.7 mmol) followed bymethanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.9 g, 7.7 mmol).The mixture was heated in a sealed vial at 100° C. over night to formprecipitate. The mixture was treated with dichloromethane and theprecipitate was filtered off and the solvent was concentrated. Theresidue was purified with a silica gel column eluted with ethyl acetatein hexanes from 0 to 30% to give precipitate (0.96 g, yield: 100%).ESI-MS: 373.30 (M)⁺.

Example 51 5-(trans-4-tert-Butyl-cyclohexyloxy)-2,3-dihydro-1H-indole

To a solution of5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester (0.92 g, 2.5 mmol) in THF (10 mL) was added 4 M HCl indioxane (6 mL, 25 mmol). The mixture was stirred at room temperature for48 hrs to form white precipitate. This mixture was partitioned betweendichloromethane and aqueous sodium bicarbonate, and the organic phasewas dried over MgSO₄, filtered and concentrated. The crude was purifiedwith a silica gel column eluted with methanol in dichloromethane from 0to 8% to give precipitate (0.67 g, yield: 99%). ESI-MS: 274.2 (M+H)⁺.

Example 523-tert-butoxycarbonylamino-4-[5-(trans-4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-4-oxo-butyricacid tert-butyl ester

To a solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole(110 mg, 0.4 mmol) in dimethylformamide (2 mL) was added HOBTmonohydrate (10 mg, 0.1 mmol), 2-tert-butoxycarbonylamino-succinic acid4-tert-butyl ester (230 mg, 0.8 mmol) and finallyN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92 mg,0.48 mmol). The reaction was heated at 50° C. overnight. The solutionwas diluted with ether and washed twice with water. The organic phasewas dried over MgSO₄, filtered and concentrated to give crude product(220 mg, yield: 100%). The crude was used directly in Example 53.ESI-MS: 545.4 (M+H)⁺.

Example 533-amino-4-[5-(trans-4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-4-oxo-butyricacid

To a solution of3-tert-butoxycarbonylamino-4-[5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-4-oxo-butyricacid tert-butyl ester (220 mg, 0.4 mmol) in dichloromethane (1 mL) wasadded trifluoroacetic acid (TFA) (0.8 mL, 10 mmol). The reaction wasstirred at room temperature over night. The solvent was concentrated andresidue was purified with HPLC to give white precipitate product TFAsalt (22 mg, yield: 13%). ESI-MS: 389.3 (M+H)⁺; ¹H NMR (400 MHz, DMSO) δ7.96 (d, 1H), 6.92 (d, 1H), 6.76(dd, 1H), 4.45 (m, 1H), 4.11-4.25 (m,3H), 3.15 (t, 2H), 3.04 (dd, 1H), 2.70 (dd, 1H), 2.09 (d, 2H), 1.77 (d,2H), 1.45 (s, 1H), 1.27 (q, 2H), 1.13 (q, 2H), 1.04 (m, 1H), 0.85 (s,9H).

Example 541-[5-(trans-4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-2-chloroethanone

A solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (0.55g, 2 mmol), triethylamine (0.56 mL, 4 mmol) in dichloromethane (8 mL)was added chloroacetyl chloride (0.2 mL, 2.6 mmol) at 0° C. The solutionwas stirred from 0° C. to room temperature for 4 hrs. The solution wasdiluted with dichloromethane and washed with 5% aqueous citric acid,aqueous sodium biocarbonate, and water, dried over MgSO₄, andconcentrated. The residue was purified with silica gel column elutedwith ethyl acetate in hexane to give product (0.37 g, yield: 52%).ESI-MS: 350.2 (M+H)⁺.

Example 55(2-{2-[5-(trans-4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-2-oxo-ethylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of1-[5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-2-chloroethanone(60 mg, 0.2 mmol) and (2-amino-ethyl)-phosphonic acid diethyl ester,oxalic acid salt (93 mg, 0.34 mmol) in dimethyl formamide (1.5 mL) wasadded lithium bromide (18 mg, 0.2 mmol) and potassium carbonate (76 mg,0.55 mmol). After being stirred at 70° C. overnight, the mixture wasdiluted with water and extracted with ethyl acetate. The organic phasewas washed with 5% aqueous citric acid, aqueous sodium biocarbonate, andwater, dried over MgSO₄ and concentrated. The residue was purified on asilica gel column to give product (20 mg, yield: 25%). ESI-MS: 495.3(M+H)⁺

Example 56(2-{2-[5-(trans-4-tert-Butyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-2-oxo-ethylamino}-ethyl)-phosphonicacid

To stirring solution of(2-{2-[5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indo-1-yl]-2-oxo-ethylamino}-ethyl)-phosphonicacid diethyl ester (16 mg, 0.03 mmol) in acetonitrile (0.5 mL) was addedbromotrimethylsilane (0.5 mL, 4 mmol). The reaction mixture was stirredat 50° C. overnight. After the solvent was concentrated, the residue waspurified by HPLC (acetonitrile-water) to give white precipitate product(7.5 mg, yield: 53%), ESI-MS: 439.2 (M+H)⁺

Example 573-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoicacid

6-bromo-2-hydxoxyquinoline was treated with cis-4-tert-butylcyclohexanolunder Mitsunobu conditions, affording6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline.6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposedto n-butyllithium and DMF, providing6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehydewas then treated with 3-aminopropionic acid and sodium cyanoborohydrideto afford the title compound,3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoicacid.

Example 583-((6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoicacid

6-hydroxy-2-methylquinoline was treated withcis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording6-((trans)-4-tert-butylcyclohexyloxy)-2-methylquinoline, which in turnwas oxidized with tert-butyl hydrogen peroxide and selenium dioxide indioxane, providing6-((trans)-4-tert-butylcyclohexyloxy)-2-formylquinoline. This aldehydewas then treated with t-butyl 3-aminopropionate and sodiumcyanoborohydride in dichloroethane to afford t-butyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)-quinolin-2-yl)methyl)amino)propionate.Treatment with lithium hydroxide in methanol/THF gave the tide compound,3-((6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoicacid.

Example 59 tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate

3-(tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv)was dissolved in DCM (100 mL). Then methanesulfonamide (1.43 g, 15.1mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g,3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h atr.t. The reaction mixture was cooled down to 0° C., ice water (100 mL)was added. The mixture was stirred for 15 min, separated and the waterlayer was extracted twice with DCM. The combined organic layer waswashed by 5% HCl, brine, dried over Na₂SO₄, concentrated to givetert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate as a gray oil (3.6g, 90%). ESI-MS (M+H)⁺: 267.1. ¹H NMR (400 MHz, DMSO-d₆) δ, 6.91˜6.83(brs, 1H), 3.36 (s, 3H), 3.19˜3.12 (m, 2H), 2.41 (t, 2H), 1.37 (s, 9H).

Example 60 3-amino-N-(methylsulfonyl)propanamide

tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate (3.6 g, 15.1 mmol)was dissolved in DCM (60 mL). Then CF₃COOH (1.1 mL, 0.3 mmol, 20 equiv )was added to the mixture at 0° C. and stirred for 2 h at 0° C. Thereaction mixture was concentrated. The residue was purified by flashchromatography to give 3-amino-N-(methylsulfonyl)propanamide as atransparent solid (1.8 g, 80%). (mobile phase: CH₃OH/H₂O=0˜5%). ESI-MS(M+1)⁺: 167.0. ¹H NMR (400 MHz, CD₃OD) δ: 3.21˜3.11 (m, 2H), 3.07 (s,3H), 2.60˜2.54 (m, 2H).

Example 613-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamide

6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96mmol, 1 equiv) and 3-amino-N-(methylsulfonyl)propanamide (239 mg, 1.19mmol, 1.5 equiv) were dissolved in anhydrous EtOH. The mixture wasstirred at 80° C. for 1 h. Then NaBH₃CN (110 mg, 1.74 mmol, 2 equiv) wasadded to the mixture and stirred at 80° C. for 16 h. The organic layerwas concentrated and purified by prep-TLC to give3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamideas a white solid (62 mg, 14%). (mobile phase; CH₃OH/DCM=1:10). ESI-MS(M+1)¹: 461.2, HPLC: 96.38%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93 (s, 1H),7.85˜7.77 (m, 2H), 7.59˜7.49 (m, 1H), 7.43-7.35(m, 1H), 7.20-7.11(m,1H), 4.45˜4.33 (m, 1H), 4.20 (s, 2H), 2.98 (t, 2H), 2.77 (s, 3H), 2.35(t, 2H), 2.26˜2.14 (m, 2H), 1.86˜1.75 (m, 2H), 1.41˜1.30 (m, 2H),1.27˜1.14 (m, 2H), 1.13˜1.02 (m, 1H), 0.89 (s, 9H).

Example 623-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamide

Preparation was done as describe in Example 61 utilizing6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehydein place of 6-((1r, 4r)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde. 71mg, white solid, yield: 17%. (mobile phase: CH3OH/DCM=1:10). ESI-MS(M+1)⁺: 529.2. HPLC: 98.69%. ¹H NMR (400 MHz, CD₃OD) δ: 8.25˜8.20 (m,1H), 8.13˜8.08 (m, 1H), 8.04˜8.01 (m, 1H), 7.68˜7.63(m, 1H),7.60˜7.55(m, 1H), 4.54˜4.43 (m, 1H), 4.40 (s, 2H), 3.36 (t, 2H), 3.24(s, 3H), 2.82 (t, 2H), 2.24˜2.16 (m, 2H), 1.94˜1.86 (m, 2H), 1.55˜1.43(m, 2H), 1.29˜1.16 (m, 2H), 1.15˜1.07 (m, 1H), 0.90 (s, 9H).

Example 63 ethyl3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoate

Ethyl3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoate,(491 mg, 1.2 mmol, 1 equiv) was dissolved in DCM (20 mL). Then Et₃N (360mg, 3.56 mmol, 3 equiv), DMAP (15 mg, 0.13 mmol, 0.1 equiv) and (Boc)₂O(520 mg, 2.38 mmol, 2 equiv) was added to the mixture and stirred for 18h at r.t. The reaction was washed by 5% HCl, brine, dried over Na₂SO₄,concentrated and purified by prep-TLC to give ethyl3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoateas a yellow oil (478 mg, 78%). (mobile phase: EA/PE=1:8). ESI-MS (M+1)⁺:512.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.71˜7.63 (m, 2H), 7.61˜7.53 (m, 1H),7.38˜7.27 (m, 1H), 7.15˜7.10 (m, 2H), 4.57 (s, 2H), 4.30˜4.21 (m, 1H),4.07 (q, 2H), 3.57˜3.37 (m, 2H), 2.60˜2.45 (m, 2H), 2.31˜2.23 (m, 2H),1.93˜1.85 (m, 2H), 1.58˜1.36 (m, 11H), 1.26˜1.04 (m, 6H), 0.89 (s, 9H).

Example 643-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoicacid

To a solution of ethyl3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoate(485 mg, 0.94 mmol) in EtOH (10 mL) was added aqueous NaOH (2 mL, 20%,5.0 equiv) and refluxed for 2 h. Then the reaction was cooled to 0° C.,the pH of the solution was adjusted to 6 using 1M HCl, concentrated andthe residue was dissolved in DCM, washed with water, dried andconcentrated to give3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoicacid as a gray oil (392 mg, 75%). ESI-MS (M+H⁺); 484.3. ¹H NMR (400 MHz,DMSO-d₆) δ: 7.79˜7.72 (m, 2H), 7.62˜7.57 (m, 1H), 7.35˜7.26 (m, 2H),7.14˜7.08 (m, 1H), 4.49 (s, 2H), 4.41˜4.30 (m, 1H), 3.38˜3.26 (m, 2H),2.33˜2.26 (t, 2H), 2.23˜2.15 (m, 2H), 1.95˜1.84 (m, 2H), 1.47˜1.28 (m,11H), 1.27˜1.15 (m, 2H), 1.11˜1.02 (m, 1H), 0.87 (s, 9H).

Example 65 tert-butyl(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl(3-(cyclopropanesulfonamido)-3-oxopropyl)carbamate

Procedure for tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate wasutilized to give tert-butyl(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl(3-(cyclopropanesulfonamido)-3-oxopropyl)carbamate.435 mg, gray oil, 100%. ESI-MS (M+1)⁺: 587.3. ¹H NMR (400 MHz, DMSO-d₆):δ 7.80˜7.73 (m, 2H), 7.64˜7.59 (m, 1H), 7.36˜7.27 (m, 2H), 7.15˜7.10 (m,1H), 4.50 (s, 2H), 4.40˜4.32 (m, 1H), 3.45˜3.45 (m, 2H), 2.94˜2.86 (m,1H), 2.56˜2.52 (m, 2H), 2.24˜2.15 (m, 2H), 1.85˜1.77 (m, 2H), 1.51˜1.27(m, 11H), 1.25˜0.99 (m, 7H), 0.87 (s, 9H)

Example 663-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(cyclopropylsulfonyl)propanamide

The procedure for 3-amino-N-(methylsulfonyl)propanamide was used to give3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(cyclopropylsulfonyl)propanamide.92 mg, white solid, 25%, ESI-MS (M+1)⁺: 487.3. ¹H NMR (400 MHz, DMSO-d₆)δ: 7.94˜7.90 (m, 1H), 7.86˜7.79 (m, 2H), 7.55˜7.50 (m, 1H), 7.41˜7.38(m, 1H), 7.20˜7.14 (m, 1H), 4.44˜4.34 (m, 1H), 4.23 (s, 2H), 3.02 (t,2H), 2.79-2.71 (m, 1H), 2.37 (t, 2H), 2.25˜2.16 (m, 2H), 1.86˜1.76 (m,2H), 1.41˜1.28 (m, 2H), 1.27˜1.15 (m, 2H), 1.11˜1.03 (m, 1H), 0.88 (s,9H), 0.83˜0.78 (m, 2H), 0.73-0.66 (m, 2H).

Example 67 ethyl2-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)acetate

Procedure was done as described in example 27 to give ethyl2-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)acetate.ESI-MS (M+H⁺): 466.3. HPLC: 92.65%. ¹H NMR (400 MHz, CD₃OD) δ: 8.09 (d,1H), 7.99 (d, 1H), 7.78 (s, 1H), 7.56 (dd, 1H), 7.45 (d, 1H), 4.43-4.36(m, 1H), 4.17 (q, 2H), 3.90 (s, 2H), 3.40 (s, 2H), 2.17 (d, 2H), 1.86(d, 2H), 1.48 (q, 2H), 1.26-1.13 (m, 5H), 1.10-1.03 (m, 1H), 0.88 (s,9H).

Example 682-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)aceticacid

Procedure was done as described in example 28 to give2-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)aceticacid. 50 mg, purified by HPLC-preparation (0.05% TFA/water: MeOH=0-95%),white solid (yield: 44%). ESI-MS (M+H⁺): 438.2 HPLC: 96.18%. ¹H NMR (400MHz, CD₃OD) δ: 8.20 (d, 1H), 8.08 (d, 1H), 7.98 (s, 1H), 7.61 (dd, 1H),7.55 (d, 1H), 4.50-4.45 (m, 1H), 4.33 (s, 2H), 3.53 (s, 2H), 2.20 (d,2H), 1.90 (d, 2H), 1.47 (q, 2H), 1.25, (q, 2H), 1.15-1.08 (m, 1H), 0.91(s, 9H).

Example 69 ethyl4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoate

Procedure was done as described in example 27 to give ethyl4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoate160 mg, purified by HPLC-preparation (0.05% TFA/water: MeOH=0˜95%),white solid (yield: 61%). ESI-MS (M+H⁺): 494.3. HPLC: 95.66%. ¹H NMR(400 MHz, CD₃OD) δ: 8.22 (d, 1H), 8.11 (d, 1H), 8.03 (s, 1H), 7.66 (dd,1H), 7.58 (d, 1H), 4.50-4.46 (m, 1H), 4.37 (s, 2H), 4.13 (q, 2H), 3.16(t, 2H), 2.49 (t, 2H), 2.21 (d, 2H), 2.04 (t, 2H), 1.90 (d, 2H), 1.49(q, 2H), 1.34-1.30 (m, 5H). 1.14-1.09 (m, 1H), 0.91 (s, 9H).

Example 704-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoicacid

To a solution of ethyl4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoate(150 mg, 0.30 mmol) in THF (15 mL) was added 1M HCl (3 mL) and refluxedfor 1 h. Then the reaction was concentrated to give4-((6-((trans)-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)butanoicacid as a white solid, purified by HPLC-preparation (0.05% TFA/water:MeOH=0˜95%), 50 mg, white solid (yield: 34%), ESI-MS (M+H⁺): 466.3 HPLC:96.13%. ¹H NMR (400 MHz, CD₃OD) δ: 8.20 (d, 1H), 8.10 (d, 1H), 8.01 (d,1H), 7.65 (dd, 1H), 7.57 (d, 1H), 4.50-4.46 (m, 1H), 4.34 (s, 2H), 3.16(t, 2H), 2.46 (d, 2H), 2.21 (d, 2H), 1.98 (t, 2H), 1.90 (d, 2H), 1.49(q, 2H), 1.25 (q, 2H), 1.14-1.08 (m, 1H), 0.91 (s, 9H).

Example 71 methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylate

A mixture of compound methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate(150 mg, 0.37 mmol) and NFSI (175 mg, 0.56 mmol, 1.5 eq.) was heated to80° C. and stirred for 4 h under N₂ atmosphere. Then the mixture waspurified by silica gel chromatography using PE/EA (6/1) as eluent togive product methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylateas a slight yellow oil (40 mg, 34%). EDI-MS (M+1)⁺: 428.1. ¹H NMR (400MHz, CDCl₃) δ 7.97 (d, 1H), 7.65-7.62 (m, 1H), 7.52-7.41 (m, 2H),7.25-7.22 (m, 1H), 4.22-4.17 (m, 1H), 3.74 (s, 2H), 3.71 (s, 3H),3.59-3.54 (m, 2H), 3.37-3.36 (m, 3H), 2.22-2.19 (m, 2H), 1.86-1.84 (m,2H), 1.54-1.45 (m, 2H), 1.19-1.08 (m, 3H), 0.86 (s, 9H).

Example 72 ethyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylate

Compound methyl1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate(140 mg, 0.34 mmol) and NCS (90 mg, 0.68 mmol, 2.0 eq.) were dissolvedin MeCN (5 mL). Then CF₃COOH (12 mg, 0.1 mmol, 0.3 eq.) was added to themixture at 0° C. The mixture was warmed to r.t. and stirred for 1 h.Then the pH of the solution was adjusted to 7 with saturated Na₂CO₃,concentrated and the mixture was extracted by EtOAc. The organic layerwas concentrated and purified by silica gel chromatography using PE/EA(6/1) to give product methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylate(65 mg, 43%) as a slight yellow oil. EDI-MS (M+1)⁺: 444.0. ¹H NMR (400MHz, CDCl₃) δ 8.16 (d, 1H), 7.69-7.66 (m, 2H), 7.50-7.47 (m, 1H),7.28-7.27 (m, 1H), 4.25-4.19 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H),3.59-3.58 (m, 2H), 3.38-3.37 (m, 3H), 2.23-2.20 (m, 2H), 1.88-1.85 (m,2H), 1.61-1.52 (m, 2H), 1.12-1.07 (m, 3H), 0.87 (s, 9H).

Example 731-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylicacid

To a solution of methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylate40 mg, 0.09 mmol) in EtOH (3 mL) was added aqueous NaOH (2 mL, 1%, 5.0eq.) and refluxed for 1 h. Then the reaction was cooled to 0° C., the pHof the solution was adjusted to 6 with 1M HCl, concentrated and theresidue was washed with DCM and water, dried in vacuum to give product1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylicacid (30 mg, 78%) as a white solid. EDI-MS (M+1)⁺: 414.0. HPLC: 91.27%.¹H NMR (400 MHz, CD₃OD) δ 8.09-8.01 (m, 2H), 7.74-7.71 (m, 1H),7.59-7.58 (m, 1H), 7.48 (t, 1H), 4.57 (s, 2H), 4.38-4.32 (m, 5H),3.76-3.70 (m, 1H), 2.21-2.19 (m, 2H), 1.91-1.88 (m, 2H), 1.53-1.44 (m,2H), 1.24-1.10 (m, 3H), 0.90 (s, 9H).

Example 741-((6-((trans)-4-tert-butylcyclohexyloxy)-5-chloronaphthalen-2-yl)methyl)azetidine-3-carboxylicacid

Procedure was done as performed for1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylicacid to give the title compound solid (35 mg, 56%). EDI-MS (M+1)⁺:430.0. HPLC: 91.27%. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.26 (m, 1H),8.00-7.90 (m, 2H), 7.64-7.53 (m, 2H), 4.49 (s, 2H), 4.45-4.38 (m, 1H),4.22-4.19 (m, 4H), 3.49-3.42 (m, 1H), 2.28-2.24 (m, 2H), 1.96-1.92 (m,2H), 1.60-1.51 (m, 2H), 1.30-1.16 (m, 3H), 0.94 (s, 9H).

Example 75 methyl 3-(benzylamino)-2-methylpropanoate

A mixture of methyl methacrylate (7 mL, 0.067 mol, 1.0 equiv),benzylamine (6 mL, 0.055 mol, 0.8 equiv) in methanol (5 mL) was stirredat 70° C. for 2 days. After evaporation of the volatiles, the crudeproduct was purified by flash chromatography (DCM: MeOH=20:1) to givecompound methyl 3-(benzylamino)-2-methylpropanoate 9 g, yield: 65%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.32-7.24 (m, 5H), 3.79 (s, 2H),3.68 (s, 3H), 2.88-2.85 (m, 1H), 2.71-2.63 (m, 2H), 1.16 (d, 3H).

Example 76 methyl 3-amino-2-methylpropanoate

To a solution of methyl 3-(benzylamino)-2-methylpropanoate (3 g, 14mmol, 1.0 equiv) and acetic acid (87 mg, 1.4 mmol, 0.1 equiv) inmethanol (30 mL) was added Pd/C (10%, 0.3 g). The resulting mixture wasstirred under hydrogen at 25° C. for 16 h. The catalyst was filteredoff, and the filtrate was concentrated to give methyl3-amino-2-methylpropanoate (1.4 g, yield: 83%) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ: 3.72 (s, 3H), 3.06-3.01 (m, 1H), 2.91-2.86 (m, 1H),2.77-2.72 (m, 1H), 1.95 (s, 2H), 1.22 (d, 3H).

Example 77 methyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-methylpropanoate

The preparation of methyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-methylpropanoatewas done as described for example 27. 110 mg, pale yellow solid, yield:35%. ESI-MS (M+H)⁺: 412.1. HPLC: 93.41%. ¹H NMR (400 MHz, CDCl₃) δ:7.70-7.65 (m, 3H), 7.34 (d, 1H), 7.10 (dd, 1H), 7.01(d, 1H), 4.16-4.09(m, 1H), 3.96 (s, 2H), 3.65 (s, 3H), 3.143-3.138 (m, 1H), 2.92, (d, 2H),2.16-2.12 (m, 2H), 1.84-1.81 (m, 2H), 1.39-1.26 (m, 2H), 1.15-1.05 (m,6H), 0.88 (s, 9H).

Example 783-((6-((trans)-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-methylpropanoicacid

The preparation of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-methylpropanoicacid was done as described for example 77. 100 mg, yellow solid, yield:94%, ESI-MS (M+H)⁺: 398.1. HPLC: 97.60%, ¹H NMR (400 MHz, CDCl₃) δ: 7.84(s, 1H), 7.72-7.68 (m, 2H), 7.59 (d, 1H), 7.15-7.10 (m, 2H), 4.33-4.24(m, 3H), 3.11-2.82 (m, 3H), 2.25-2.21 (m, 2H), 1.89-1.86 (m, 2H),1.48-1.11 (m, 9H), 0.89 (s, 9H).

Example 79 ethyl 2-cyano-2-methylpropanoate

A solution of ethyl 2-cyanoacetate (3 g, 0.026 mol, 1.0 equiv) intetrahydrofuran (80 mL) was cooled at ice-salt bath, followed by theaddition of sodium hydride (2.6 g, 0.104 mol, 4.0 equiv) in severalportions. The suspension was stirred at r.t. Then iodomethane (11 g,0.078 mmol, 3.0 equiv) was added and the reaction mixture was stirred atr.t for 3 h before quenched with water. The mixture was extracted withethyl acetate and washed with brine, dried over Na₂SO₄ and concentratedto obtain crude product ethyl 2-cyano-2-methylpropanoate (3.2 g, yield:85%) as a dark green oil. ¹H NMR (400 MHz, CDCl₃) δ: 4.27 (q, 2H), 1.62(s, 6H), 1.34 (t, 3H).

Example 80 ethyl 3-amino-2,2-dimethylpropanoate

To a solution of ethyl 2-cyano-2-methylpropanoate (0.6 g, 4.2 mmol, 1.0equiv) in 6 mL of ethanol/ammonium hydroxide (10:1) was added Ra/Ni(20%, 0.12 g). The resulting mixture was stirred under hydrogen at r.t.for 16 h. The catalyst was filtered off, and the filtrate wasconcentrated in give ethyl 3-amino-2,2-dimethylpropanoate (4.3 g, yield:70%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 4.15 (q, 2H), 2.77 (s,2H), 1.76 (s, 2H), 1.26 (t, 3H), 1.18 (s, 6H).

Example 81 ethyl3-((6-(trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylpropanoate

The preparation of ethyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylpropanoatewas performed as described in example 27. 230 mg, colorless oil, yield:68%. ESI-MS (M+H)⁺: 440.1. HPLC: 89.40%. ¹H NMR (400 MHz, CDCl₃) δ:7.70-7.65 (m, 3H), 7.42 (d, 1H), 7.13-7.11 (m, 2H), 4.29-4.23 (m, 1H),4.12 (q, 2H), 3.95 (s, 2H), 2.70 (s, 2H), 2.29-2.26 (m, 2H), 1.91-1.88(m, 2H), 1.48-1.42 (m, 2H), 1.25-1.09 (m, 12H), 0.90 (s, 9H).

Example 823-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylpropanoicacid

The preparation of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-dimethylpropanoicacid was performed as described in example 28. 210 mg, pale yellowsolid, yield: 98%. ESI-MS (M+H)⁺: 412.1. HPLC: 96.40%. ¹H NMR (400 MHz,CDCl₃) δ: 7.75 (s, 1H), 7.69-7.67 (m, 2H), 7.58 (d, 1H), 7.14-7.09 (m,2H), 4.26-4.21 (m, 3H), 2.78 (s, 2H), 2.24-2.22 (m, 2H), 1.89-1.86 (m,2H), 1.45-1.37 (m, 2H), 1.28-1.08 (m, 9H), 0.89 (s, 9H).

Example 83 6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthonitrile

Compound 2-bromo-6-((trans)-4-tert-butylcyclohexyloxy)naphthalene (2.0g, 5.55 mmol, 1.0 eq,) and CuCN (742 mg, 8.34 mmol, 1.5 eq.) wasdissolved in DMSO (5 mL). Then the mixture was stirred at 125° C. for 15h. Water was added and the mixture was extracted with ethyl acetate andthe organic layer was purified by silica gel column chromatography usingPE/EA (10/1) to give product as a slight yellow solid (1.423 g, 82%).EDI-MS (M+1)⁺: 308.0 ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.78-7.73(m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H),2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m,3H), 0.91 (s, 9H).

Example 84(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine

Compound 6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthonitrile (1.7 g,5.53 mmol, 1.0 eq.) and NH₄OH (0.3 mL, 6.65 mmol, 1.2 eq.) was dissolvedin MeOH (5 mL). Then Raney Ni (64 mg, 1.11 mmol, 0.2 eq,) was added tothe mixture and the suspension solution was stirred at r.t. underhydrogen atmosphere for 15 h. The mixture was filtrated and purified bysilica gel column chromatography using DCM/MeOH (10/1) as eluent to giveproduct as a pale solid (1.76 g, 63%). ESI-MS (M-NH₂)⁺: 295.1. ¹H NMR(400 MHz, CDCl₃) δ 7.71-7.65 (m, 3H), 7.38 (dd, 1H), 7.15-7.11 (m, 2H),4.28-4.24 (m, 1H), 3.98 (s, 2H), 2.30-2.26 (m, 2H), 1.91-1.87 (m, 2H),1.76 (s, 2H), 1.46-1.40 (m, 2H), 1.21-1.12 (m, 3H), 0.90 (s, 9H).

Example 85 ethyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxypropanoate

(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311mg, 1.0 mmol, 1.0 eq.) and ethyl oxirane-2-carboxylate (116 mg, 1.0mmol, 1.0 eq.) was dissolved in EtOH (5 mL). Then the mixture wasrefluxed for 2 h. The mixture was concentrated and purified by silicagel column chromatography using DCM/MeOH (10/1) as eluent to giveproduct as a slight yellow oil (311 mg, 35%), EDI-MS (M+1)⁺: 428.1.HPLC: 92.02%. ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.64 (m, 3H), 7.38 (dd,1H), 7.13-7.11) (m, 2H), 4.31-4.21 (m, 4H), 3.93 (q, 2H), 3.06-2.88 (AB,2H), 2.60 (b, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.41 (m,2H), 1.26 (t, 3H), 1.20-1.09 (m, 3H), 0.89 (s, 9H).

Example 863-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxypropanoicacid

The preparation of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxypropanoicacid was done as described for example 28. 50 mg, white solid, yield:38%. ESI-MS (M+H)⁺: 400.2. HPLC: 99.87%. ¹H NMR (400 MHz, CD₃OD) δ:7.46-7.36 (m, 3H), 7.24 (s, 1H), 6.93-6.87 (m, 2H), 4.23-4.20 (m, 1H),4.04-4.02 (m, 1H), 3.72 (s, 2H), 2.94-2.92 (m, 2H), 2.10-2.07 (m, 2H),1.75-1.73 (m, 2H), 1.31-1.24 (m, 2H), 1.07-1.01 (m, 3H), 0.89 (s, 9H).

Example 87 ethyl 1-cyanocyclopropanecarboxylate

Ethyl 2-cyanoacetate (0.85 g, 7.5 mmol, 1 equiv), 1,2-dibromoethane (1.3mL, 15 mmol, 2 equiv) and K₂CO₃ (3.18 g, 22.5 mmol, 3 equiv) wasdissolved in acetone (6 mL), and the mixture was stirred for 16 h at 80°C. The reaction mixture was filtered, concentrated to give the crudeproduct as a yellow oil (1.84 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ:4.18 (t, 2H), 1.75 (t, 2H), 1.60 (m, 2H), 1.20 (t, 3H).

Example 88 ethyl 1-(aminomethyl)cyclopropanecarboxylate

The preparation of ethyl 1-(aminomethyl)cyclopropanecarboxylate as ayellow oil (783 mg, 73%) was performed as described for the synthesis ofethyl 3-amino-2,2-dimethylpropanoate (Example 80). ESI-MS (M+1)⁺: 144.1.¹H NMR (400 MHz, DMSO-d₆) δ: 4.03 (t, 2H), 3.59 (s, 2H), 1.17 (t, 3H),0.99 (t, 2H), 0.84 (t, 2H).

Example 89 ethyl1-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclopropanecarboxylate

The preparation of ethyl1-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclopropanecarboxylatewas performed as described in example 27 as a slight yellow oil (211 mg,37%). ESI-MS (M+1)⁺: 438.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.73˜7.64 (m,3H), 7.45˜7.39 (m, 1H), 7.19˜7.09 (m, 2H), 4.31˜4.20 (m, 1H), 4.16˜4.07(m, 2H), 3.66 (s, 2H), 2.73˜2.71 (m, 2H), 2.31˜2.23 (m, 2H), 1.93˜1.85(m, 2H), 1.50˜1.36 (m, 2H), 1.29˜1.04 (m, 8H), 0.89 (s, 9H), 0.82˜0.76(m, 2H).

Example 901-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclopropanecarboxylicacid

The preparation of1-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)methyl)cyclopropanecarboxylicacid was performed as described for example 28 as a white solid (162 mg,94%). ESI-MS (M+1)⁺: 410.3. HPLC: 97.07%. ¹H NMR (400 MHz, DMSO-d₆) δ:7.93˜7.73 (m, 3H), 7.59˜7.50 (m, 1H), 7.42˜7.36 (m, 1H), 7.19˜7.10 (m,1H), 4.43˜4.33 (m, 1H), 4.20˜4.09 (brs, 2H), 3.00˜2.89 (m, 2H),2.26˜2.14 (m, 2H), 1.85˜1.75 (m, 2H), 1.40˜1.29 (m, 2H), 1.27˜1.14 (m,3H), 1.13˜1.00 (m, 2H), 0.96˜0.76 (m, 11H).

Example 91N-((6-(trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine

6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (200 mg, 0.64mmol, 1 equiv), ethanamine (58 mg, 1.05 mmol, 2 equiv) and AcOH (62 mg,1.05 mmol, 2 equiv) were dissolved in DCM (15 mL), and the mixture wasstirred at r.t. for 2 h. Then NaBH₃CN (101 mg, 1.9 mmol, 3 equiv) wasadded to the mixture and stirred for 16 h at r.t. The reaction mixturewas washed by brine, dried over Na₂SO₄, and concentrated to give thetitle compound as a gray oil (250 mg, 100%). ESI-MS (M+1)⁺: 340.3. ¹HNMR (400 MHz, CDCl₃) δ: 7.73˜7.63 (m, 3H), 7.42˜7.31 (m, 1H), 7.16˜7.09(m, 2H), 4.30˜4.21 (m, 1H), 3.91 (s, 2H), 2.73 (q, 2H), 2.31˜2.23 (m,2H), 1.93˜1.83 (m, 2H), 1.49˜1.36 (m, 2H), 1.27˜1.18 (m, 2H), 1.15 (t,3H), 1.12˜1.05 (m, 1H), 0.89 (s, 9H).

Example 92 methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(ethyl)amino)propanoate

N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine(250 mg, 0.64 mmol, 1 equiv) was dissolved in CH₃OH (1 mL). Then methylacrylate (4 mL, 44 mmol, 70 equiv) was added to the mixture and stirredat r.t. for 16 h. The reaction was concentrated and purified by prep-TLCto give the title compound as a white solid (217 mg, 52%). (mobilephase: EA/PE=1:8). ESI-MS (M+1)⁺: 426.3, HPLC: 97.34%. ¹H NMR (400 MHz,CDCl₃) δ: 7.71˜7.60 (m, 3H), 7.44˜7.38 (m, 1H), 7.16˜7.09 (m, 2H),4.30˜4.20 (m, 1H), 3.69 (s, 2H), 3.64 (s, 3H), 2.85 (t, 2H), 2.65˜2.46(m, 4H), 2.31˜2.24 (m, 2H), 1.92˜1.85 (m, 2H), 1.49˜1.37 (m, 2H),1.30˜1.10 (m, 3H), 1.05 (t, 3H), 0.89 (s, 9H).

Example 933-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(ethyl)amino)propanoicacid

The preparation of3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(ethyl)amino)propanoicacid was performed as described for example 28 to give the titlecompound as a white solid (126 mg, 60%). ESI-MS (M+1)⁺: 412.3. HPLC:96.12%, ¹H NMR (400 MHz, DMSO-d₆) δ: 7.91 (m, 1H), 7.84˜7.76 (m, 2H),7.61˜7.55 (m, 1H), 7.40˜7.31 (m, 1H), 7.18˜7.12 (m, 1H), 4.43˜4.34 (m,1H), 4.12 (s, 2H), 3.03 (t, 2H), 2.90˜2.78 (m, 2H), 2.66 (t, 2H),2.25˜2.17 (m, 2H), 1.86˜1.76 (m, 2H), 1.41˜1.29 (m, 2H), 1.25˜1.12 (m,5H), 1.10˜1.02 (m, 1H), 0.89 (s, 9H).

Example 94N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)propan-1-amine

The preparation ofN-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)propan-1-aminewas done as described forN-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine(Example 91) to give the title compound as a gray oil (429 mg, 100%).ESI-MS (M+H)⁺: 354.3. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.76˜7.66 (m, 3H),7.44˜7.40 (m, 1H), 7.32˜7.30 (m, 1H), 7.12˜7.06 (m, 1H), 4.40˜4.30 (m,1H), 3.78 (s, 2H), 2.46 (t, 2H), 2.23˜2.15 (m, 2H), 1.85˜1.76 (m, 2H),1.44 (q, 2H), 1.39˜1.27 (m, 2H), 1.26˜1.15 (m, 3H), 0.87 (s, 9H), 0.86(t, 3H).

Example 95 methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(propyl)amino)propanoate

The preparation of methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(propyl)amino)propanoatewas performed as described for methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(ethyl)amino)propanoate(Example 93) to give the title compound as a white solid (195 mg, 46%).(mobile phase: EA/PE═1:8). ESI-MS (M+1)⁺: 440.3. HPLC: 95.63%. ¹H NMR(400 MHz, CDCl₃) δ: 7.71˜7.60 (m, 3H), 7.44˜7.39 (m, 1H), 7.16˜7.09 (m,2H), 4.30˜4.20 (m, 1H), 3.67 (s, 2H), 3.64 (s, 3H), 2.83 (t, 2H), 2.50(t, 2H), 2.41 (t, 2H), 2.31˜2.23 (m, 2H), 1.93˜1.84(m, 2H), 1.55˜1.37(m, 4H), 1.25˜1.05 (m, 3H), 0.89 (s, 9H), 0.84 (t, 3H).

Example 963-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(propyl)amino)propanoicacid

The preparation of3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(propyl)amino)propanoicacid was same performed as described for example 28 as a white solid(147 mg, 78%) ESI-MS (M+1)⁺: 426.3. HPLC: 99.49%. ¹H NMR (400 MHz,DMSO-d₆) δ: 7.86˜7.76 (m, 3H), 7.55˜7.49 (m, 1H), 7.39˜7.34 (m, 1H),7.17˜7.10 (m, 1H), 4.43˜4.33 (m, 1H), 4.02 (s, 2H), 2.96 (t, 2H),2.70˜2.55 (m, 4H), 2.24˜1.16 (m, 2H), 1.86˜1.76 (m, 2H), 1.63˜1.53 (m,2H), 1.40˜1.28 (m, 2H), 1.26˜1.14 (m, 2H), 1.07˜1.02 (m, 1H), 0.89 (s,9H), 0.82 (t, 3H).

Example 97N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclobutanamine

The preparation ofN-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclobutanaminewas performed as described for example 27 to give the title compound asa gray oil (282 mg, 100%). ESI-MS (M+H)⁺: 366.3. ¹H NMR (400 MHz, CDCl₃)δ: 7.76˜7.62 (m, 3H), 7.43˜7.37 (m, 1H), 7.17˜7.08 (m, 2H), 4.31˜4.19(m, 1H), 3.82 (s, 2H), 3.37˜3.29 (m, 1H), 2.37˜2.18 (m, 4H), 1.98˜1.84(m, 4H), 1.76˜1.67 (m, 2H), 1.49˜1.36 (m, 2H), 1.26˜1.04 (m, 3H), 0.89(s, 9H).

Example 98 methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclobutyl)amino)propanoate

The synthesis of methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclobutyl)amino)propanoatewas performed as described for methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(ethyl)amino)propanoate(Example 95) to give the title compound as a white solid (240 mg, 55%).(mobile phase: EA/PE=1:8). ESI-MS (M+1)⁺: 452.3. HPLC: 97.45%. ¹H NMR(400 MHz, CDCl₃) δ: 7.72˜7.58 (m, 3H), 7.44˜7.38 (m, 1H), 7.15˜7.09 (m,2H), 4.30˜4.20 (m, 1H), 3.62 (s, 2H), 3.60 (s, 3H), 3.20˜3.11 (m, 1H),2.75 (t, 2H), 2.41 (t, 2H), 2.31˜2.23 (m, 2H), 1.95˜1.83 (m, 4H),1.71˜1.52 (m, 2H), 1.50˜1.31 (m, 2H), 1.26˜1.05 (m, 5H), 0.89 (s, 9H).

Example 993-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclobutyl)amino)propanoicacid

The preparation of3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclobutyl)amino)propanoicacid was performed as described for example 28 to give the titlecompound as a white solid (152 mg, 65%) ESI-MS (M+1)⁺: 438.3. HPLC:98.55%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.78˜7.66 (m, 3H), 7.44˜7.37 (m,1H), 7.34˜7.30 (m, 1H), 7.14˜7.06 (m, 1H), 4.41˜4.31 (m, 1H), 3.64 (s,2H), 3.22˜3.14 (m, 1H), 2.64 (t, 2H), 2.35 (t, 2H), 2.25˜2.14 (m, 2H),2.03˜1.93 (m, 2H), 1.90˜1.76 (m, 4H), 1.64˜1.49 (m, 2H), 1.40˜1.27 (m,2H), 1.26˜1.14 (m, 2H), 1.10˜1.01 (m, 1H), 0.87 (s, 9H).

Example 100N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclopentanamine

The preparation ofN-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclopentanaminewas performed as described in example 27 to give the title compound as agray oil (356 mg, 100%). ESI-MS (M+H)⁺: 380.3. ¹H NMR (400 MHz, CDCl₃)δ: 7.73˜7.63 (m, 3H), 7.44˜7.39 (m, 1H), 7.15˜7.08 (m, 2H), 4.30˜4.20(m, 1H), 3.90 (s, 2H), 3.18˜3.10 (m, 1H), 2.31˜2.22 (m, 2H), 1.93˜1.84(m, 2H), 1.78˜1.06 (m, 13H), 0.89 (s, 9H).

Example 101 methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclopentyl)amino)propanoate

The synthesis of methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclopentyl)amino)propanoatewas performed as described for methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclobutyl)amino)propanoate(Example 98) to give the title compound as a white solid (258 mg, 69%).(mobile phase: EA/PE=1:8) ESI-MS (M+1)⁺: 466.3. HPLC: 95.23%. ¹H NMR(400 MHz, CDCl₃) δ: 7.72˜7.61 (m, 3H), 7.45˜7.40 (m, 1H), 7.16˜7.08 (m,2H), 4.30˜4.21 (m, 1H), 3.72 (s, 2H), 3.60 (s, 3H), 3.15˜3.06 (m, 1H),2.87 (t, 2H), 2.45 (t, 2H), 2.31˜2.24 (m, 2H), 1.93˜1.85 (m, 2H),1.83˜1.73 (m, 2H), 1.69˜1.61 (m, 2H), 1.54˜1.36 (m, 6H), 1.26˜1.03 (m,3H), 0.89 (s, 9H).

Example 1023-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclopentyl)amino)propanoicacid

The preparation of3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclopentyl)amino)propanoateacid was performed as described for example 28 to give the titlecompound as a white solid (171 mg, 58%) ESI-MS (M+H)⁺: 452.3. HPLC:95.83%. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.01˜7.93 (m, 1H), 7.86˜7.77 (m,2H), 7.70˜7.64 (m, 1H), 7.43˜7.37 (m, 1H), 7.21˜7.14 (m, 1H), 4.45˜4.35(m, 1H), 4.28 (s, 2H), 3.58˜3.45 (m, 1H), 3.11˜3.01 (m, 2H), 2.75˜2.62(m, 2H), 2.26˜2.14 (m, 2H), 2.06˜1.93 (m, 2H), 1.90˜1.77 (m, 4H),1.76˜1.65 (m, 2H), 1.59˜1.47 (m, 2H), 1.40˜1.30 (m, 2H), 1.27˜1.16 (m,2H), 1.12˜1.02 (m, 1H), 0.88 (s, 9H).

Example 103N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclohexanamine

The preparation ofN-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclohexanaminewas performed as described for example 27 to give the title compound asa white solid (420 mg, 95%). ESI-MS (M+H)⁺: 394.2. ¹H NMR (400 MHz,CDCl₃) δ: 7.82-7.70 (m, 3H), 7.47-7.45 (m, 1H), 7.15-7.07 (m, 2H),4.23-4.17 (m, 1H), 4.06 (s, 2H), 2.86-2.80 (m, 1H), 2.22-2.18 (m, 2H),1.89-1.85 (m, 2H), 1.73-1.59 (m, 4H), 1.43-1.08 (m, 11H), 0.90 (s, 9H).

Example 104 methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)cyclohexyl)amino)propanoate

The synthesis of methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclohexyl)amino)propanoatewas performed as described for methyl3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)((cyclobutyl)amino)propanoate(Example 98) to give the title compound as a white solid (80 mg, 16%)(mobile phase: EA/PE=1:8). ESI-MS (M+H)⁺: 480.2. ¹H NMR (400 MHz, CDCl₃)δ: 7.74-7.62 (m, 3H), 7.44-7.41 (m, 1H), 7.14-7.09 (m, 2H), 4.29-4.23(m, 1H), 3.74 (s, 2H), 3.60 (s, 3H), 2.86 (t, 2H), 2.49-2.39 (m, 3H),2.29-2.26 (m, 2H), 1.91-1.78 (m, 5H), 1.56-1.10 (m, 12H), 0.90 (s, 9H).

Example 1053-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclohexyl)amino)propanoicacid

The preparation of3-(((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(cyclohexyl)amino)propanoicacid was performed as described for example 28 to give the titlecompound, 65 mg, slight yellow solid, yield: 84%. ESI-MS (M+H)⁺: 466.1.HPLC: 96.99%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.86-7.77 (m, 3H), 7.54 (d,1H), 7.38 (d, 1H), 7.15 (dd, 1H), 4.41-4.35 (m, 1H), 4.10 (br, 2H), 3.04(t, 2H), 2.86-2.84 (m, 1H), 2.22-2.19 (m, 2H), 1.97-1.94 (m, 2H),1.83-1.75 (m, 4H), 1.57-1.07 (m, 13H), 0.88 (s, 9H).

Example 106 methyl 2-(hydroxymethyl)acrylate

A saturated aqueous solution (10 mL) of K₂CO₅ (3.5 g, 117 mmol, 1.6 eq.)was slowly added to a rapidly stirred solution oftrimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) andparaformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t. After the additionthe mixture was stirred for 2 h. Then the mixture was extracted withDCM. The organic layer was concentrated to give the compound (1.5 g,44%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ: 6.29 (s, 1H), 5.83 (s,1H), 3.75 (s, 3H), 3.72 (s, 2H).

Example 107 methyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-(hydroxymethyl)propanoate

Compounds(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311mg, 1.0 mmol, 1.0 eq.) and methyl 2-(hydroxymethyl)acrylate (116 mg, 1.0mmol, 1.0 eq.) was dissolved in MeOH (5 mL). The mixture was stirred atr.t. for 2 h. Then the mixture was concentrated and purified by silicagel column chromatography using DCM/CH₃OH (10/1) to give product (250mg, 58%) as a slight yellow oil. ESI-MS (M+H)⁺: 428.3. HPLC: 90.18%. ¹HNMR (400 MHz, CDCl₃) δ 7.68 (t, 2H), 7.63 (s, 1H), 7.37 (dd, 1H),7.14-7.11 (m, 2H), 4.27-4.25 (m, 1H), 4.01-3.96 (m, 2H), 3.91 (s, 2H),3.71 (s, 3H), 3.18-2.93 (AB, 2H), 2.73-2.71 (m, 1H), 2.28-2.25 (m, 2H),1.90-1.87 (m, 2H), 1.45-1.40 (m, 2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H).

Example 1083-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-(hydroxymethyl)propanoicacid

The preparation of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-(hydroxymethyl)propanoicacid was performed as described for example 28 to give the titlecompound 50 mg, white solid, yield: 21%. ESI-MS (M+H)⁺: 414.3. HPLC:94.23%. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.52 (d, 1H), 7.43 (d,1H), 7.37-7.35 (m, 1H), 6.93 (d, 1H), 6.88 (s, 1H), 4.07-4.05 (m, 1H),3.95 (s, 2H), 3.73-3.61 (m, 2H), 3.04-2.83 (AB, 2H), 2.74-2.72 (m, 1H),2.12-2.09 (m, 2H), 1.79-1.76 (m, 2H), 1.32-1.25 (m, 2H), 1.09-1.01 (m,3H), 0.85 (s, 9H).

Example 109 ethyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)cyclobutanecarboxylate

The preparation of ethyl3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)cyclobutanecarboxylatewas performed as described for example 27 to give the title compoundESI-MS (M+H)⁺: 438.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.73˜7.63 (m, 3H),7.42˜7.37 (m, 1H), 7.15˜7.08 (m, 2H), 4.29˜4.21 (m, 1H), 4.11 (q, 2H),3.85 (d, 2H), 3.30˜3.24 (m, 1H), 2.75˜2.69 (m, 1H), 2.53˜2.46 (m, 2H),2.30˜2.22 (m, 2H), 2.05˜1.98 (m, 2H), 1.92˜1.85 (m, 2H), 1.47˜1.38 (m,2H), 1.27˜1.15 (m, 5H), 1.14˜1.05 (m, 1H), 0.89 (s, 9H).

Example 1103-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)cyclobutanecarboxylicacid

The preparation of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)cyclobutanecarboxylicacid was performed as described for example 28 to give the titlecompound ESI-MS (M+1)⁺: 410.3. HPLC: 96.18%. ¹H NMR (400 MHz, CD₃OD) δ7.85˜7.73 (m, 3H), 7.47˜7.41 (m, 1H), 7.26˜7.21 (m, 1H), 7.16˜7.08 (m,1H), 4.37˜4.28 (m, 1H), 4.15˜4.07 (m, 2H), 3.65˜3.54 (m, 1H), 2.84˜2.77(m, 1H), 2.58˜2.51 (m, 2H), 2.30˜2.18 (m, 4H), 1.93˜1.85 (m, 2H),1.46˜1.33 (m, 2H), 1.30˜1.18 (m, 2H), 1.13˜1.08 (m, 1H), 0.89 (s, 9H).

Example 111 (S)-methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-2-carboxylate

The preparation of (S)-methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-2-carboxylatewas performed as described for example 27 to give the title compound.ESI-MS (M+1)⁺: 424.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.70˜7.64 (m, 3H), 7.45(d, 1H), 7.13˜7.09 (m, 2H), 4.28˜4.23 (m, 1H), 4.06˜4.00 (m, 1H),3.77-3.71 (m, 1H), 3.61 (s, 3H), 3.33-3.31 (m, 1H), 3.11-3.07 (m, 1H),2.45-2.41 (m, 1H), 2.27 (d, 2H), 2.20-2.16 (m, 1H), 2.01-1.96 (m, 1H),1.89 (d, 2H), 1.73-1.69 (m, 2H), 1.46-1.42 (m, 2M), 1.23-1.09 (m, 3H),0.89 (s, 9H).

Example 112(S)-1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-2-carboxylicacid

The preparation of(S)-1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-2-carboxylicacid was performed as described for example 28 to give the titlecompound as a white solid (50 mg, 70%). ESI-MS (M+1)⁺: 410.3. HPLC:98.10%. ¹H NMR (400 MHz, CD₃OD) δ: 7.95 (s, 1H), 7.86 (d, 1H), 7.83 (d,1H), 7.54 (dd, 1H), 7.29 (d, 1H), 7.19 (dd, 1H), 4.69 (d, 1H), 4.46-4.37(m, 3H), 3.62˜3.54 (m, 1H), 3.44-3.40 (m, 1H), 2.66-2.62 (m, 1H), 2.28(d, 2H), 2.25-2.16 (m, 2H), 2.02-1.98 (m, 1H), 1.93 (d, 2H), 1.46-1.41(m, 2H), 1.30-1.25 (m, 2H), 1.17˜1.13 (m, 1H), 0.91 (s, 9H).

Example 113 methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-2-carboxylate

The preparation of methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-2-carboxylatewas performed as described for example 27 to give the title compound.ESI-MS (M+1)⁺: 410.3. ¹H NMR (400 MHz, CD₃OD) δ: 7.73˜7.66 (m, 3H), 7.38(dd, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.37˜4.31 (m, 1H), 3.93-3.83 (m,1H), 3.73 (d, 2H), 3.56 (s, 3H), 3.29-3.21 (m, 1H), 3.13-3.08 (m, 1H),2.29˜2.25 (m, 4H), 1.92 (d, 2H), 1.45-1.40 (m, 2H), 1.30˜1.09 (m, 3H),0.93 (s, 9H).

Example 1141-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-2-carboxylicacid

The preparation of1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-2-carboxylicacid was performed as described for example 28 to give the titlecompound as a white solid (50 mg, 70%), ESI-MS (M+1)⁺: 396.3. HPLC:96.99%. ¹H NMR (400 MHz, CD₃OD) δ: δ: 7.82 (s, 1H), 7.75 (d, 2H), 7.43(dd, 1H), 7.14 (d, 2H), 4.94-4.90 (m, 1H), 4.49-4.41 (m, 2H), 4.30-4.23(m, 1H), 4.06-4.01 (m, 1H), 3.86-3.81 (m, 1H), 2.64-2.59 (m, 2H), 2.23(d, 2H), 1.87 (d, 2H), 1.44-1.38 (m, 2H), 1.22˜1.07 (m, 3H), 0.86 (s,9H).

Example 115 tert-butyl3-amino-3-oxopropyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)carbamate

The mixture of3-(tert-butoxycarbonyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propanoicacid (483 mg, 1.0 mmol), NH₄Cl (21.5 mg, 5.0 mmol, 5.0 equiv), Et₃N (510mg, 5.0 mmol, 5.0 equiv) and HATU (760 mg, 2.0 mmol, 2.0 equiv) inanhydrous THF (20 mL) was stirred at 45° C. for 15 min. The reactionmixture was concentrated in vacuum and the residue was purified bychromatography with silica gel (DCM/MeOH=20/1) to give compound thetitle compound as a white solid (337 mg, yield: 70%), ESI-MS (M+H)⁺:483.3. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.76 (d, 2H), 7.60 (s, 1H), 7.34 (s,1H), 7.30 (d, 1H), 7.12 (dd, 1H), 4.49 (s, 2H), 4.38-4.31 (m, 1H), 3.30(t, 2H), 2.30 (t, 2H), 2.19 (d, 2H), 1.81 (d, 2H), 1.45-1.33 (m, 11H),1.23-1.16 (m, 3H), 0.88 (s, 9H).

Example 116N-acetyl-3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanamide

The mixture of tert-butyl3-amino-3-oxopropyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)carbamate(241 mg, 0.5 mmol) in Ac₂O and AcOH (6 mL, 1:5), was stirred at 90° C.for 2 h. The reaction mixture was concentrated in vacuum and the residuewas purified by chromatography with silica gel (DCM/MeOH=15/1) to givethe title compound as a white solid (100 mg, yield: 50%), ESI-MS (M+H⁺):425.3. HPLC: 94.82%. ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (d, 1H), 7.68 (d,1H), 7.49 (s, 1H), 7.21 (d, 1H), 7.17-7.14 (m, 2H), 6.50 (br, 1H), 5.49(br, 1H), 4.71 (s, 2H), 4.24-4.30 (m, 1H), 3.71 (t, 2H), 2.57 (t, 2H),2.27 (d, 2H), 2.18 (s, 3H), 1.89 (d, 2H), 1.48-1.42 (m, 2H), 1.09-1.20(m, 3H), 0.88 (s, 9H).

Example 116 6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthonitrile

To a vial charged with 6-hydroxy-2-naphthonitrile (3.38 g, 0.02 mol, 1.0eq,), cis-4-tert-butylcyclohexanol (6.24 g, 0.04 mol, 2.0 eq.), PPh₃(10.5 g, 0.04 mol, 2.0 eq.) and toluene (20 mL), was added DIAD (12 mL,0.06 mol, 3.0 eq.) under nitrogen atmosphere at r.t. and stirred for 15h. Water was added and extracted with EtOAc. The organic layer waspurified by silica gel chromatography (PE:EA=10:1) to give the titlecompound (9.0 g, 86%) as a slight yellow solid. EDI-MS (M+1)⁺: 308.0. ¹HNMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H),7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H),1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).

Example 1172-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-amine

To a vial charged with6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthonitrile (500 mg, 1.63mmol, 1.0 eq.), CeCl₃ (1.2 g, 4.89 mmol, 3.0 eq.) and THF (10 mL), wasadded MeLi (1.5 M solution in diethoxymethane, 10 mL, 16.3 mmol, 10.0eq.) under nitrogen atmosphere at −78° C. The mixture was stirred at−78° C. for 1 h. Saturated ammonium chloride solution was added andextracted with EtOAc. The organic layer was purified by silica gelchromatography (DCM: MeOH−10:1) to give the title compound (140 mg, 25%)as a slight yellow oil. ¹NMR (400 MHz, CDCl₃) δ: 7.84 (S, 1H), 7.72-7.66(m, 2H), 7.59 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4.23 (m, 1H), 2.29 (b,2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.61 (s, 6H), 1.48-1.39 (m,2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H).

Example 118 methyl3-(2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-ylamino)propanoate

2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-amine(113 mg, 0.33 mmol, 1.0 eq,) and methyl acrylate (86 mg, 0.99 mmol, 3.0eq.) was dissolved in MeOH (2 mL). The mixture was reflux for 16 h. Themixture was concentrated and purified by silica gel chromatography(DCM:MeOH=20:1) to give the title compound (100 mg, 71%) as a slightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.73-7.68 (m, 3H), 7.60 (dd, 1H),7.13-7.16 (m, 2H), 4.26-4.23 (m, 1H), 3.66 (s, 3H), 2.62 (t, 2H), 2.50(t, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.58 (s, 6H), 1.45-1.38(m, 2H), 1.19-1.09 (m, 3H), 0.89 (s, 9H).

Example 1193-(2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-ylamino)propanoicacid

The preparation of3-(2-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-2-ylamino)propanoicacid was performed as described in example 28 to give the title compoundas a white solid (75 mg, 78%). HPLC: 96.91%. ¹H NMR (400 MHz, CD₃OD) δ:7.97 (s, 1H), 7.89-7.83 (m, 2H), 7.64 (dd, 1H), 7.27 (s, 1H), 7.17 (dd,1H), 4.39-4.36 (m, 1H), 2.94 (t, 2H), 2.58 (t, 2H), 2.29-2.27 (m, 2H),1.94-1.92 (m, 2H), 1.90 (s, 6H), 1.45-1.41 (m, 2H), 1.32-1.13 (m, 3H),0.92 (s, 9H).

Example 1202-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)acetonitrile

6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (310 mg, 1 mmol),2-aminoacetonitrile (112 mg, 2 mmol, 2.0 eq) and acetic acid (180 mg, 3mmol, 3.0 eq) in DCE (10 mL) was stirred at rt for 10 min. ThenNaBH(OAc)₃ (636 mg, 3 mmol, 3.0 eq) was added to the mixture and themixture was stirred at rt for 15 h. Then saturated NaHCO₃ was added tothe mixture until pH=8. The mixture was extracted with DCM (20 mL×3).The organic layer was concentrated and the residue was purified bysilica gel column chromatography eluting with DCM/CH₃OH (20/1) to giveproduct the title compound as a colorless oil (240 mg, yield: 69%).ESI-MS (M+H⁺): 351.2. ¹H NMR (400 MHz, CDCl₃) δ: 7.70 (dd, 2H), 7.68 (s,1H), 7.41 (dd, 1H), 7.13 (d, 2H), 4.30-4.23 (m, 1H), 4.05 (s, 2H), 3.57(s, 2H), 2.26 (d, 2H), 1.90 (d, 2H), 1.48-1.42 (m, 2H), 1.20-1.09 (m,3H), 0.90 (s, 9H).

Example 121N-((1H-tetrazol-5-yl)methyl)-1-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine

To a solution of2-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)acetonitrile(240 mg, 0.69 mmol) in water and isopropanol (10 mL, 1:5) was added NaN₃(50 mg, 0.76 mmol, 1.1 eq) and ZnBr₂ (153 mg, 0.69 mmol, 1.0 eq), thenrefluxed for 18 h. The reaction was cooled to 0° C. and saturated NaHCO₃was added. The mixture was extracted with DCM (20 mL×3) and the aqueouslayer was destroyed by NaClO solution. The organic layer wasconcentrated and the residue was the title compound as a white solid (27mg, yield: 11%). ESI-MS (M+H⁺): 394.3. HPLC: 91.15%, ¹H NMR (400 MHz,CD₃OD) δ: 7.82 (s, 1H), 7.79-7.72 (m, 2H), 7.42 (d, 1H), 7.16 (d, 2H),4.47-4.31 (m, 5H), 2.26 (d, 2H), 1.89 (d, 2H), 1.45-1.41 (m, 2H),1.24-1.09 (m, 3H), 0.88 (s, 9H)

Example 1223-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanenitrile

Procedure was followed as described for2-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)acetonitrile(Example 120) to give the title compound 240 mg, white solid (yield:62%). ESI-MS (M+H³⁰ ): 365.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (dd, 2H),7.66 (s, 1H), 7.40 (dd, 1H), 7.13 (d, 2H), 4.30-4.23 (m, 1H), 3.95 (s,2H), 2.97 (t, 2H), 2.56 (t, 2H), 2.29 (d, 2H), 1.90 (d, 2H), 1.46-1.42(m, 2H), 1.20-1.12 (m, 3H), 0.90 (s, 9H)

Example 123N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-2-(1H-tetraxol-5-yl)ethanamine

The procedure was followed as described for N-((1H-tetrazol-5-yl)methyl)-1-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine(Example 121) to give the title compound 20 mg, white solid (yield:11%), ESI-MS (M+H³⁰ ): 408.3 HPLC: 98.66% ¹H NMR (400 MHz, CD₃OD) δ:7.93 (s, 1H), 7.85 (dd, 2H), 7.53 (dd, 1H), 7.30 (d, 1H) 7.19 (dd, 1H),4.45 (s, 2H), 4.42-4.36 (m, 1H), 3.61 (t, 2H), 3.43 (t, 2H), 2.29 (d,2H), 1.93 (d, 2H), 1.43-1.39 (m, 2H), 1.33-1.11 (m, 3H), 0.88 (s, 9H)

Example 1243-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanamide

To a solution of3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanenitrile(233 mg, 0.64 mmol) in DMSO (2 mL) was added K₂CO₃(265 mg, 2 mmol, 3.0eq), the mixture was then cooled to 0° C., and followed by addition ofaq. 30% H₂O₂ (0.3 mL). The reaction mixture was stirred at rt for 1 h,and quenched with water (10 mL). The solvent was removed byfreezen-dried. The crude product was purified by flash chromatography togive the title compound as a white solid (111 mg, 45%) (mobile phase:MeOH/H₂O: 0%˜80%). ESI-MS (M+1)⁺: 383.3. HPLC: 97.84%. ¹H NMR(400 MHz,CD₃OD) δ: 7.86˜7.79 (m, 3H), 7.53˜7.50 (m, 1H), 7.33˜7.30 (m, 1H),7.21˜7.16 (m, 1H), 4.42˜4.35 (m, 3H), 3.34˜3.27 (m, 2H), 2.71 (t, 2H),2.32˜2.24 (m, 2H), 1.96˜1.87 (m, 2H), 1.51˜1.39 (m, 2H), 1.33˜1.20 (m,2H), 1.17˜1.09 (m, 1H), 0.92 (s, 9H).

Example 125 methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-iodonaphthalen-2-yl)methyl)azetidine-3-carboxylate

Methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(410 mg, 1 mmol) and NIS (247 mg, 1.1 mmol, 2.0 e.q.) were dissolved inCH₃ON (5 mL). Then CF₃COOH (35 mg, 0.3 mmol, 0.3 eq,) was added to themixture dropwise at 0° C. The mixture was warmed to r.t. and stirred foranother 1.5 h. Then the mixture was extracted with EtOAc and the organiclayer was concentrated and purified by silica gel chromatography usingPE/EA (1/1) as eluent to give product the title compound as a slight redsolid (300 mg, 56%). ESI-MS (M+H³⁰ ): 536.2. ¹H NMR (400 MHz, CDCl₃) δ:8.19 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.22 (d, 1H),4.34-4.28 (m, 4H), 3.91-3.67 (m, 1H), 3.80-3.78 (m, 3H), 3.75 (s, 3H),2.24-2.21 (m, 2H), 1.90-1.88 (m, 2H), 1.62-1.58 (m, 2H), 1.15-1.12 (m,3H), 0.89 (s, 9H).

Example 126 methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)methyl)azetidine-3-carboxylate

A flask charged with compound methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-iodonaphthalen-2-yl)methyl)azetidine-3-carboxylate(300 mg, 0.56 mmol), methylboronic acid (66 mg, 1.1 mmol, 2.0 eq), 2 Maq K₂CO₃ (5 mL, 3.0 equiv) and[1,1-bis(diphenylphosphino)ferroene]dichloropalladium (II) complex withdichloromethane (1:1) (45 mg, 0.05 mmol, 0.1 equiv) was flushed withnitrogen. 1,4-Dioxane (20 mL) was added and the reaction was stirred at90° C. for 5 h. The solution was cooled to room temperature. The solventwas removed and the residue was purified by column chromatography(PE/EA=1:1) to give compound the title compound as a white solid (80 mg,33%). ESI-MS (M+H³⁰ ): 424.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (d, 1H),7.64-7.61 (m, 2H), 7.40 (dd, 1H), 7.23 (d, 1H), 4.10-4.08 (m, 1H), 3.79(s, 2H), 3.74 (s, 3H), 3.59-3.56 (m, 2H), 3.39-3.36 (m, 3H), 2.53 (s,3H), 2.20-2.17 (m, 2H), 1.86-1.83 (m, 2H), 1.48-1.43 (m, 2H), 1.10-1.26(m, 3H), 0.86 (s, 9H)

Example 1271-((6-((trans)-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)methyl)azetidine-3-carboxylicacid

To a solution of methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)methyl)azetidine-3-carboxylate(80 mg, 0.18 mmol) in EtOH (10 mL) was added aqueous NaOH (2 mL, 20%,5.0 eq) and 85° C. for 1 h. Then the reaction was cooled to 0° C., thepH of the solution was adjusted to 6 using 1 M HCl, concentrated and theresidue was dissolved in DCM, washed with water, dried and concentratedto give the title compound as a white solid (40 mg, yield: 52%). ESI-MS(M+H³⁰ ): 410.3. HPLC: 97.77% ¹H NMR (400 MHz, CD₃OD) δ: 8.04 (d, 1H),7.92 (s, 1H), 7.77 (d, 1H), 7.50 (dd, 1H), 7.41 (d, 1H), 4.54 (s, 2H),4.34-4.26 (m, 5H), 3.74-3.70 (m, 1H), 2.52 (s, 3H), 2.21-2.18 (m, 2H),1.91-1.88 (m, 2H), 1.49-1.44 (m, 2H), 1.23-1.11 (m, 3H), 0.90 (s, 9H).

Example 128 (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane

To a solution of compound 6-bromonaphthalen-2-ol (10 g, 0.044 mol, 1.0equiv) and imidazole (6 g, 0.088 mol, 2.0 equiv) in dry DMF (100 mL) wasadded TBDMSCl (10 g, 0.066 mol, 1.5 equiv) at 0° C. Then the reactionmixture was warmed to r.t and stirred for 3 h. Then DMF was removedunder reduced pressure. The mixture was extracted with ethyl acetate andwashed with brine, dried over Na₂SO₄ and concentrated to obtain crudeproduct. The crude product was purified by silica gel chromatography(PE:EA=30:1) to give compound to give the title compound as a yellowsolid (23 g, 76%). ESI-MS (M+H)⁺: 336.9. ¹H NMR (400 MHz, CDCl₃) δ:7.91-7.92 (m, 1H), 7.64-7.46 (m, 3H), 7.15-7.08 (m, 2H), 1.01 (s, 9H),0.24 (s, 6H).

Example 129 6-(tert-butyldimethylsilyloxy)-2-naphthaldehyde

To a solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane(4 g, 0.01 mol, 1.0 equiv) in dry THF (30 mL) at −78° C. under N₂atmosphere was added n-BuLi (2.5 M, 12 mL, 3.0 equiv) dropwise andstirred for 30 min. Then DMF (7.3 g, 0.1 mol, 10 equiv) was added andstirred for another 1 h, then quenched with water, extracted with ethylacetate and washed with brine, dried over Na₂SO₄ and concentrated toobtain crude product. The crude product was purified by silica gelchromatography (PE:EA=20:1) to give compound the title compound (2.2 g,64%) as a yellow liquid. ESI-MS (M+1)⁺: 287.0 ¹H NMR (400 MHz, CDCl₃) δ:10.10 (s, 1H), 8.26 (s, 1H), 7.91-7.88 (m, 2H), 7.78-7.76 (m, 1H),7.24-7.16 (m, 2H), 1.03 (s, 9H), 0.28 (s, 6H).

Example 130 methyl1-((6-(tert-butyldimethylsilyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

6(-tert-butyldimethylsilyloxy)-2-naphthaldehyde (4.0 g, 14 mmol), AcOH(1.8 g, 28 mmol) and methyl azetidine-3-carboxylate (3.2 g, 28 mmol, 2.0equiv) in DCE (30 mL) were stirred at 85° C. for 1 h. Then NaBH₃CN (1.8g, 28 mmol, 2.0 equiv) was added to the mixture at 50° C. and stirredfor 2 h at 85° C. The reaction mixture was quenched with water,extracted with DCM and washed with brine, dried over Na₂SO₄ andconcentrated to obtain crude product. The crude product was purified bysilica gel chromatography (DCM:MeOH=40:1) to give the title compound(2.7 g, 50%) as a yellow oil. ESI-MS (M+1)⁺: 386.2. ¹H NMR (400 MHz,CDCl₃) δ: 7.72-7.68 (m, 3H), 7.37-7.34 (m, 1H), 7.15-7.10(m, 2H), 3.94(s, 2H), 3.81-3.76 (m, 4H), 3.74 (s, 3H), 3.50-3.44 (m, 1H), 1.02 (s,9H), 0.25 (s, 6H).

Example 131 methyl1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate

To a solution of methyl1-((6-(tert-butyldimethylsilyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(4.5 g, 11.7 mmol) in methanol (50 mL) at 0° C. was added con. HCl (5mL) dropwise. The reaction mixture was stirred at r.t for 1 h. Themixture was neutralized by sat. NaHCO₃ and evaporated off most ofsolvent, extracted with DCM and washed with brine, dried over Na₂SO₄ andconcentrated to obtain crude product. The crude product was purified bysilica gel chromatography (DCM:MeOH=40:1), extracted with DCM and washedwith brine, dried over Na₂SO₄ and concentrated to obtain crude product.The crude product was purified by silica gel chromatography(DCM:MeOH=40:1) to give the title compound (1.5 g, 47%) as a gray solid.ESI-MS (M+1)⁺: 272.0. ¹H NMR (400 MHz, CDCl₃) δ: 8.14 (s, 1H), 7.59-7.52(m, 2H), 7.39-7.28 (m, 2H), 7.09-7.04 (m, 2H), 3.92 (s, 2H), 3.86-3.82(m, 2H), 3.70 (s, 3H), 3.63-3.59 (m, 2H), 3.52-3.46 (m, 1H).

Example 132 methyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

To a vial was added methyl1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (271 mg, 1.0mmol), 4-(trifluoromethyl)cyclohexanol (252 mg, 1.5 mmol, 1.5 equiv),PPh₃ (524 mg, 2.0 mmol, 2.0 equiv) and toluene (0.8 mL) under N₂atmosphere. While stirring, DIAD (404 mg, 2.0 mmol, 2.0 equiv) was addedto the reaction mixture quickly at r.t and stirred for 10 min. Thereaction mixture was then purified by silica gel chromatography(PE:EA=5:1) to give the title compound (114 mg, 28%) as a slight yellowoil. ESI-MS (M+1)⁺: 408.2. ¹H NMR (400 MHz, CD₃OD) δ: 7.76 (d, 1H),7.70(d, 1H), 7.66 (s, 1H), 7.36 (dd, 1H), 7.24 (d, 1H), 7.17 (dd, 1H),4.86-4.76 (m, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H),3.32-3.34 (m, 3H), 2.33-2.22 (m, 1H), 2.20 (d, 2H), 1.82-1.67 (m, 6H).

Example 133 methyl1-((6-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 100 mg, slight yellow oil, yield: 27% ESI-MS (M+1)⁺:351.2. ¹H NMR (400 MHz, CD₃OD) δ: 7.72 (d, 1H), 7.70 (d, 1H), 7.66 (s,1H), 7.36 (dd, 1H), 7.16 (d, 1H), 7.08 (dd, 1H), 4.67-4.61 (m, 1H), 3.75(s, 2H), 3.72 (s, 3H), 3.55 (t, 2H), 3.44 (t, 2H), 3.39-3.35 (m, 1H),2.45 (q, 2H), 1.97-1.93 (m, 2H), 1.44-1.40 (m, 2H), 0.51-0.48 (m, 1H),0.20 (q, 1H).

Example 134 methyl1-((6-(bi(cyclohexan)-4-yloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 100 mg, slight yellow oil, yield: 26% ESI-MS (M+1)⁺:435.3 ¹H NMR (400 MHz, CD₃OD) δ: 7.76-7.70 (m, 2H), 7.66 (s, 1H), 7.36(dd, 1H), 7.21 (d, 1H), 7.10 (dd, 1H), 4.33-4.39 (m, 1H), 3.77 (s, 2H),3.72 (s, 3H), 3.57 (t, 2H), 3.46 (t, 2H), 3.39-3.35 (m, 1H), 2.26 (d,2H), 1.89-1.40 (m, 9H), 1.30-1.09 (m, 9H)

Example 135 methyl1-((6-(cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 100 mg, slight yellow oil, yield: 20%. ESI-MS (M+1)⁺:354.2 ¹H NMR (400 MHz, CDCl₃) δ: 7.71-7.63 (m, 3H), 7.37 (dd, 1H), 7.13(dd, 2H), 5.01-4.95 (m, 2H), 4.42-4.36 (m, 1H), 3.78-3.76 (m, 2H), 3.71(s, 3H), 3.63-3.61 (m, 1H), 3.40-3.38 (m, 2H), 2.07 (d, 2H), 1.82 (d,2H), 1.60-1.54 (m, 3H), 1.43-1.37 (m, 3H)

Example 136 methyl1-((6-((trans)-4-cyclopentylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 217 mg, slight yellow oil, yield: 46%. ESI-MS (M+1)⁺:422.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.73˜7.59 (m, 3H), 7.38˜7.31 (m, 1H),7.16˜7.08 (m, 2H), 4.32˜4.22 (m, 1H), 3.72 (s, 2H), 3.71 (s, 3H),3.57-3.56 (m, 2H), 3.38-3.34 (m, 3H), 2.26˜2.17 (m, 2H), 1.96˜1.87 (m,2H), 1.83˜1.71 (m, 2H), 1.68˜1.39 (m, 12H).

Example 137 methyl1-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132), 67 mg, slight yellow oil, yield: 17%, ESI-MS (M+1)⁺:410.3 ¹H NMR (400 MHz, CDCl₃) δ: 7.72-7.65 (m, 3H), 7.38 (d, 1H), 7.16(dd, 2H), 4.68-6.66 (m, 1H), 3.80 (s, 2H), 3.72 (s, 3H), 3.66-3.64 (m,2H), 3.42-3.40 (m, 3H), 2.18 (d, 2H), 1.59-1.49 (m, 7H), 0.89 (s, 9H)

Example 138 methyl1-((6-(4-methylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 216 mg, slight yellow oil, yield: 64%. ESI-MS (M+1)⁺:368.2. ¹H NMR (400 MHz, CDCl₃) δ: 7.74˜7.61 (m, 3H), 7.38˜7.32 (m, 1H),7.18˜7.08 (m, 2H), 4.66˜4.24 (m, 1H), 3.75 (s, 2H), 3.71 (s, 3H),3.62˜3.52 (m, 2H), 3.43˜3.31 (m, 3H), 2.23˜2.01 (m, 2H), 1.65˜1.56 (m,2H), 1.54˜1.38 (m, 5H), 0.99˜0.90 (m, 3H).

Example 139 methyl1-((6-(4-propylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). ESI-MS (M+1)⁺: 396.3. ¹H NMR (400 MHz, CDCl₃) δ:7.72-7.66 (m, 3H), 7.37 (d, 1H), 7.16-7.12 (m, 2H), 4.76-4.66 (m, 1H),3.74-3.66 (m, 5H), 3.59-3.52 (m, 2H), 3.40-3.33 (m, 3H), 2.25-1.85 (m,2H), 1.60-1.55 (m, 11H), 0.90 (t, 3H).

Example 140 methyl1-((6-(4-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). 292 mg, slight yellow oil, yield: 76%. ESI-MS (M+1)⁺:410.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.73˜7.60 (m, 3H), 7.39˜7.32 (m, 1H),7.18˜7.09 (m, 2H), 4.67˜4.20 (m, 1H), 3.75 (s, 2H), 3.71 (s, 3H),3.65˜3.52 (m, 2H), 3.42˜3.33 (m, 3H), 2.25˜2.05 (m, 2H), 1.92˜1.83 (m,2H), 1.61˜1.37 (m, 6H), 1.17˜0.98 (m, 5H), 0.93˜0.80 (m, 3H).

Example 141 methyl1-((6-(4-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(Example 132). ESI-MS (M+1)⁺: 424.3. ¹H NMR (400 MHz, CD₃OD) δ:7.73-7.64 (m, 3H), 7.34 (dd, 1H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.40-4.30(m, 1H), 3.76-3.66 (m, 5H), 3.55-3.32 (m, 5H), 2.28-2.25 (m, 2H),1.85-1.82 (m, 2H), 1.39-1.27 (m, 7H), 0.91-0.81 (m, 9H).

Example 142 (trans)-methyl 4-hydroxycyclohexanecarboxylate

To a solution of (trans)-4-hydroxycyclohexanecarboxylic acid (4.32 g, 30mmol) in MeOH (20 mL) was added SOCl₂ (7.08 g, 60 mmol, 2.0 eq) dropwiseat rt. Then the mixture was stirred at 70° C. for 18 h, and the solventwas removed in vacuo to give the title compound as a colorless oil (4.74g, yield: 100%). ¹H NMR (400 MHz, DMSO-d₆) δ: 4.33 (br, 1H), 3.68-3.60(m, 1H), 3.57 (s, 3H), 2.37-2.31 (m, 1H), 1.82-1.74 (m, 2H), 1.53-1.45(m, 6H).

Example 143 (trans)-methyl4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate

To a solution of (trans)-methyl 4-hydroxycyclohexanecarboxylate (4.74 g,30 mmol) and THP (3.06 g, 3.6 mmol, 1.2 eq) in DCM (20 mL) was addedp-TsOH (1.18 g, 6 mmol, 0.2 eq) slowly at rt. Then the mixture wasstirred at rt for 18 h, and the solvent was removed in vacuo. Theresidue was purified on silica gel (EA/PE=1:20) to give the titlecompound as a colorless oil (3.12 g, yield: 43%). ¹H NMR (400 MHz,CDCl₃) δ: 4.68 (t, 1H), 3.91-3.88 (m, 1H), 3.84-3.81 (m, 1H), 3.67 (s,3H), 3.51-3.46 (m, 1H), 2.40-2.36 (m, 1H), 2.00-1.82 (m, 4H), 1.76-1.51(m, 10H).

Example 1442-((trans)-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)propan-2-ol

To a solution of (trans)-methyl4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanecarboxylate (3.12 g, 13 mmol)in THF (10 mL) was added MeLi (65 mL, 1 M, 5.0 eq) dropwise at −78° C.,then the mixture was stirred at −78° C. for 2 h. Water (20 mL) was addedand the mixture was extracted with EA (30 mL×3), dried and concentrated.The residue was purified on silica gel (EA/PE=1:10) to give the titlecompound as a colorless oil (1.56 g, yield: 50%). ¹H NMR (400 MHz,CDCl₃) δ: 4.65 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 2.05-1.84(m, 3H), 1.73-1.68 (m, 1H), 1.59-1.53 (m, 7H), 1.35-1.31 (m, 4H), 1.17(d, 6H).

Example 1452-((trans)-4-(2-methoxypropan-2-yl)cyclohexyloxy)tetrahydro-2H-pyran

To a solution of2-((trans)-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)propan-2-ol (1.56g, 6.5 mmol) in THF (10 mL) was added NaH (300 mg, 13 mmol, 2.0 eq)slowly at r.t. and then CH₃I (1.96 g, 13 mmol, 2.0 eq) was added in oneportion. The mixture was stirred at 50° C. for 2 h. Water (10 mL) wasadded and the mixture was extracted with EA (30 mL×3), dried andconcentrated to give the title compound as a colorless oil (1.2 g,yield: 72%). ¹H NMR (400 MHz, CDCl₃) δ: 4.64 (t, 1H), 3.93-3.89 (m, 2H),3.51-3.47 (m, 1H), 3.17 (s, 3H), 1.97-1.85 (m, 3H), 1.70-1.67 (m, 1H),1.58-1.43 (m, 9H), 1.34-1.27 (m, 2H), 1.09 (d, 6H).

Example 146 (trans)-4-(2-methoxypropan-2-yl)cyclohexanol

To a solution of2-((trans)-4-(2-methoxypropan-2-yl)cyclohexyloxy)tetrahydro-2H-pyran(1.2 g, 4.7 mmol) in MeOH (10 mL) was added p-TsOH (8.9 g, 4.7 mmol, 1.0eq) slowly at rt. Then the mixture was stirred at rt for 2 h, and thesolvent was removed in vacuo. The residue was purified on silica gel(EA/PE=1:3) to give the title compound as a colorless oil (660 mg,yield: 82%). ¹H NMR (400 MHz, CDCl₃) δ: 4.07-4.05 (m, 1H), 3.17 (s, 3H),1.87-1.82 (m, 2H), 1.55-1.38 (m, 7H), 1.10 (s, 6H).

Example 147 methyl1-((6-((trans)-4-(2-methoxypropan-2-yl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate.ESI-MS (M+1)⁺: 426.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.80-7.75 (m, 3H), 7.37(d, 1H), 7.17-7.14 (m, 2H), 4.32-4.26 (m, 1H), 3.73-3.68 (m, 10H), 3.20(s, 3H), 2.30-2.28 (m, 2H), 1.89-1.87 (m, 2H), 1.69-1.65 (m, 2H),1.48-1.42 (m, 3H), 1.12 (s, 6H).

Example 148 methyl1-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate.ESI-MS (M+1)⁺: 396.3. ¹H NMR (400 MHz, CD₃OD) δ: 7.73-7.64 (m, 3H), 7.38(dd, 1H), 7.20-7.17 (m, 2H), 4.29-4.25 (m, 1H), 3.82 (s, 2H), 3.73-3.67(m, 5H), 3.45-3.39 (m, 3H), 2.30-2.10 (m, 2H), 1.85-1.82 (m, 2H),1.52-1.43 (m, 4H), 1.27-1.15 (m, 2H), 0.90 (d, 6H).

Example 1491-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

To a solution of methyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate(100 mg, 0.26 mmol) in EtOH (15 mL) was added aqueous NaOH (3 mL, 20%,5.0 eq.) and refluxed for 1 h. Then the reaction was cooled to 0° C.,the pH of the solution was adjusted to 6 using 1 M HCl, concentrated andthe residue was dissolved in DCM, washed with water, dried andconcentrated to give the title compound as a slight yellow solid (50 mg,yield: 52%). ESI-MS (M+1)⁺: 408.2 HPLC: 94.97%. ¹H NMR (400 MHz, CD₃OD)δ: 7.77 (d, 1H), 7.69 (d, 1H), 7.64 (s, 1H), 7.33 (d, 1H), 7.31 (s, 1H),7.16 (dd, 1H), 4.80-4.71 (m, 1H), 3.57 (s, 2H), 3.25 (t, 2H), 3.09 (t,2H), 2.79-2.73 (m, 1H), 2.41 (br, 1H), 2.07 (d, 2H), 1.80-1.60 (m, 6H).

Example 1501-((6-((trans)-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

(trans)-4-(1,1-difluoroethyl)cyclohexyl methanesulfonate (WO 2010051030)(0.98 mmol, 236 mg, 1.0 eq.), methyl1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (1.17 mmol,317 mg, 1.2 mmol) and Cs₂CO₃ (4.41 mmol, 1.4 g, 4.5 eq.) were dissolvedin t-butanol (4 mL) and 2-butanone (2 mL). The mixture was stirred at110° C. for 16 h, 1 M aq. HCl solution was added to the mixture toadjust pH=6. Then the mixture was extracted with EtOAc. The organiclayer was purified by silica gel column chromatography using DCM/CH₃OH(10/1) as eluent to give product (7 mg, 1.8%) as a white solid. ESI-MS(M+1)⁺: 404.1. HPLC: 89.46%. ¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H),7.86-7.81 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.47 (s,2H), 4.43-4.41 (m, 1H), 4.21 (d, 4H), 3.45˜3.41 (m, 1H), 2.32-2.30 (m,2H), 2.02-1.99 (m, 2H), 1.64-1.54 (m, 3H), 1.51-1.45 (m, 3H), 1.36-1.28(m, 2H).

Example 1511-((6-((trans)-4-(1,1-difluoropropyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described for1-((6-((trans)-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid (Example 150). 22 mg, slight yellow solid, yield: 10%. ESI-MS(M+1)⁺: 418.1. HPLC: 93.94%. ¹H NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H),7.87-7.82 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.53 (s,2H), 4.44-4.40 (m, 1H), 4.34 (d, 4H), 3.74˜3.69 (m, 1H), 2.32-2.30 (m,2H), 1.98-1.85 (m, 5H), 1.51-1.46 (m, 4H), 1.02 (t, 3H).

Example 1521-((6-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 50 mg, slight yellow solid, yield: 60%. ESI-MS (M+1)⁺: 338.2.HPLC: 97.96%. ¹H NMR (400 MHz, CD₃OD) δ: 7.85 (s, 1H), 7.80-7.78 (m,2H), 7.45 (d, 1H), 7.19 (dd, 1H), 7.14 (s, 1H), 4.65-4.58 (m, 1H), 4.41(s, 2H), 4.21-4.15 (m, 4H), 3.39-3.37 (m, 1H), 2.48 (q, 2H), 2.04-1.98(m, 2H), 1.46-1.42 (m, 2H), 0.56-0.53 (m, 1H), 0.17-0.15 (m, 1H).

Example 1531-((6-(bi(cyclohexan)-4-yloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 50 mg, slight yellow solid, yield: 58%. ESI-MS (M+1)⁺: 422.3 HPLC:93.30%. ¹H NMR (400 MHz, CD₃OD) δ: 7.81-7.77 (m, 3H), 7.41 (d, 1H), 7.20(s, 2H), 4.75-4.72 (m, 1H), 4.33 (s, 2H), 4.16-4.14 (m, 2H), 4.08-4.06(m, 2H), 3.39-3.37 (m, 1H), 2.27 (d, 2H), 1.91-1.46 (m, 9H), 1.30-1.02(m, 9H)

Example 1541-((6-(cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 50 mg, slight yellow solid, yield: 65%, ESI-MS (M+1)⁺: 340.2 HPLC:95.48%. ¹H NMR (400 MHz, CD₃OD) δ: 7.76-7.73 (m, 3H), 7.39 (d, 1H), 7.16(dd, 2H), 4.45-4.40 (m, 1H), 4.21 (s, 2H), 3.97 (br, 4H), 3.37-3.32 (m,1H), 2.04 (dd, 2H), 1.83 (dd, 2H), 1.63-1.48 (m, 3H), 1.46-1.33 (m, 3H)

Example 1551-((6-((trans)-4-cyclopentylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid, 78 mg, slight yellow solid, yield: 46%. ESI-MS (M+1)⁺: 408.3 HPLC:98.97%. ¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.83 (dd, 2H), 7.44(dd, 1H), 7.27 (d, 1H), 7.18 (dd, 1H), 4.51 (s, 2H), 4.42-4.37 (m, 1H),4.33-4.31 (m, 4H), 3.72-3.64 (m, 1H), 2.21 (dd, 2H), 1.95 (dd, 2H)1.83-1.78 (m, 2H), 1.65˜1.42 (m, 7H), 1.22˜1.14 (m, 5H)

Example 1561-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 27 mg, slight yellow solid, yield: 77%. ESI-MS (M+1)⁺: 396.3 HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.85 (dd, 2H), 7.45 (dd,1H), 7.29 (d, 1H), 7.24 (dd, 1H), 4.77-4.75 (m, 1H), 4.47 (s, 2H),4.22-4.20 (m, 4H), 3.45-3.40 (m, 1H), 2.20 (d, 2H), 1.65-1.49 (m, 6H),1.20-1.14 (m, 1H), 0.93 (s, 9H)

Example 1571-((6-(4-methylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 83 mg, slight yellow solid, yield: 40%, ESI-MS (M+1)⁺: 354.2 HPLC:96.69%. ¹H NMR (400 MHz, CD₃OD) δ: 7.87 (s, 1H), 7.81 (dd, 2H), 7.43(dd, 1H), 7.25 (d, 1H), 7.20 (dd, 1H), 4.73-4.69 (m, 1H), 4.50 (s, 2H),4.35-4.30 (m, 4H), 3.71˜3.64 (m, 1H), 2.02-1.98 (m, 2H), 1.83-1.38 (m,7H), 0.94 (d, 3H).

Example 1581-((6-(4-propylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 65 mg, yield: 69% ESI-MS (M+1)⁺: 382.2 HPLC: 96.32%. ¹H NMR (400MHz, CD₃OD) δ: 7.85-7.78 (m, 3H), 7.43 (dd, 1H), 7.22-7.15 (m, 2H),4.75-4.71 (m, 1H), 4.36 (s, 2H), 4.12-4.10 (m, 4H), 3.41-3.36 (m, 1H),2.23-1.86 (m, 2H), 1.68-1.57 (m, 3H), 1.46-1.24 (m, 8H), 0.93 (t, 3H).

Example 1591-((6-(4-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 60 mg, slight yellow solid, yield: 31%. ESI-MS (M+1)⁺: 396.3 HPLC:98.15%. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.94 (s, 1H), 7.85 (dd, 2H), 7.53(dd, 1H), 7.39 (dd, 1H), 7.20 (dd, 1H), 4.76-4.74 (m, 1H), 4.45 (s, 2H),4.15-4.13 (m, 4H), 3.66-3.60 (m, 1H), 2.16 (d, 1H), 1.95 (d, 1H), 1.82(d, 1H), 1.64-1.11 (m, 12H), 0.90 (t, 3H).

Example 1601-((6-((trans)-4-tert-pentylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 50 mg, yield: 63% ESI-MS (M+1)⁺: 410.3 HPLC: 93.22%. ¹H NMR (400MHz, CD₃OD) δ: 7.91-7.82 (m, 3H), 7.46 (dd, 1H), 7.29 (d, 1H), 7.19 (dd,1H), 4.53 (s, 2H), 4.39-4.34 (m, 5H), 3.74-3.70 (m, 1H), 2.30-2.27 (m,2H), 1.89-1.86 (m, 2H), 1.45-1.26 (m, 7H), 0.85-0.88 (m, 9H).

Example 1611-((6-((trans)-4-(2-methoxypropan-2-yl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 60 mg, yield: 52% SI-MS (M+1)⁺: 412.2 PLC: 92.12%. ¹H NMR (400MHz, CD₃OD) δ: 7.80-7.75 (m, 3H), 7.37 (d, 1H), 7.17-7.14 (m, 2H),4.36-4.30 (m, 3H), 4.13-4.07 (m, 4H), 3.36-3.31 (m, 1H), 3.19 (s, 3H),2.29-2.26 (m, 2H), 1.88-1.85 (m, 2H), 1.59-1.10 (m, 3H), 1.31-1.21 (m,2H), 1.14 (s, 6H).

Example 1621-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid

The preparation of the title compound was performed as described formethyl1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylicacid. 0 mg, yield: 72% SI-MS (M+1)⁺: 382.2 PLC: 92.20%, ¹H NMR (400 MHz,CD₃OD) δ: 7.83-7.76 (m, 3H), 7.40 (dd, 1H), 7.23-7.15 (m, 2H), 4.39-4.34(m, 3H), 4.16-4.11 (m, 4H), 4.38-4.34 (m, 1H), 2.26-2.10 (m, 2H),1.87-1.84 (m, 1H), 1.61-1.43 (m, 5H), 1.22-1.16 (m, 2H), 0.94-0.90 (m,6H).

Example 163 6-Methoxy-2-methyl-4-trifluoromethyl-quinoline

A solution of 4-Bromo-6-methoxy-2-methyl-quinoline (0.202 g, 0.801mmol). Hexamethylphosphoramide (697 uL, 3.97 mmol) inN,N-Dimethylformamide (4.30 mL) was degassed by stirring under vacuumand replacing the vacuum with Argon (4 times). To this was addedCopper(I) iodide (263 mg, 1.38 mmol) and Methylfluorosulphonyldifluoroacetate (520 uL, 3.97 mmol) and the reaction wasstirred under an atmosphere of Argon for 2 h@55° C., then at 80° C. for16 hours. The reaction was evaporated, then diluted with methylenechloride. Silica gel was added and the solvent removed. The material waspurified by silica gel chromatography using 0-50% ethyl acetate inhexanes as eluent (Rf=0.78 in 1:1 ethyl acetate/hexanes) to give theproduct in 40.5 mg yield (21%). ESI-MS (M+H+): 242.10.

Example 164 2-Methyl-4-trifluoromethyl-quinolin-6-ol

6-Methoxy-2-methyl-4-trifluoromethyl-quinoline (0.894 g, 3.71 mmol) wasdissolved in Methylene chloride (60 mL), and cooled to −78° C. Asolution of 1.0 M of Boron tribromide in Methylene chloride (11.0 mL,11.0 mmol) was then added dropwise. The reaction mixture was then warmedup to 23° C. The reaction was allowed to stir 22 h at room temperature.After cooling in an ice bath, saturated sodium bicarbonate solution wasadded with stirring. The mixture was extracted with methylene chlorideand ethyl acetate. The organics were dried over sodium sulfate, filteredand evaporated. The residue was purified by silica gel chromatographyusing 0-15% methanol in methylene chloride to give the product (Rf=0.49in 10% methanol in methylene chloride) in 771 mg yield (92%). ESI-MS((M+H+): 228.10.

Example 1656-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline

2-Methyl-4-trifluoromethyl-quinolin-6-ol (0.771 g, 0.00339 mol,cis-4-tert-Butyl-cyclohexanol (0.8570 g, 0.005484 mol) andTriphenylphosphine (1.423 g, 0.005425 mol) were placed in a flask, anddissolved in Toluene (25 mL). For the Mitsunobu reaction of certainanalogs, THF was substituted for toluene as solvent. Diisopropylazodicarboxylate (1.137 mL, 0.005430 mol) was then added dropwise. After3 d stirring at RT, the reaction was evaporated to dryness. The residuewas purified by silica gel chromatography using 0-30% ethyl acetate inhexanes as eluent (Rf=0.38 in 3:1 hexanes/ethyl acetate). Isolated was0.739 g of product (60%). ESI-MS (M+H+): 366.20.

Example 1666-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinoline-2-carbaldehyde

Di-tert-butyl peroxide (0.186 mL, 1.01 mmol) was added to a suspensionof Selenium dioxide (0.252 g, 2.27 mmol) in 1,4-Dioxane (6.0 mL). Themixture was stirred for 30 minutes, then6-(4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline(0.366 g, 1.00 mmol) was added as a solution in 1,4-Dioxane (2.0 mL).The mixture was sealed and was heated at 50° C. for 20 h. The reactionwas filtered through Celite and washed with dioxane. The solvent wasevaporated and the residue was purified on silica gel column using 0-20%ethyl acetate in hexanes as eluent. Isolated was (Rf=0.70 in 3:1hexanes/ethyl acetate) the product (212 mg, 56%). ESI-MS (M+H+): 380.20.

Example 1671-[6-trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester

N,N-Diisopropylethylamine (39 uL, 0.22 mmol) was added to a solution of6-(4-trans-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinoline-2-carbaldehyde(61 mg, 0.16 mmol) and Azetidine-3-carboxylic acid methyl esterhydrochloride salt (34 mg, 0.22 mmol) in 1,2-Dichloroethane (2.50 mL)and the mixture was stirred for 1 hour at room temperature. Sodiumtriacetoxyborohydride (54 mg, 0.25 mmol) was then added and stirring wascontinued. After 1.5 h, the reaction was diluted in methylene chlorideand washed with saturated aq. sodium bicarbonate. The organic phase wasdried over magnesium sulfate, filtered, evaporated and purified by flashchromatography (0-5% methanol in methylene chloride) to give the product(Rf=0.30 in 5% methanol/methylene chloride) in 65.8 mg yield (86%).ESI-MS (M+H+): 479.30.

Example 1681-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-(trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid

2 M of Lithium hydroxide, monohydrate in Water (0.500 mL, 1.00 mmol) wasadded to a solution of1-[6-(4-trans-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester (0.0658 g, 0.137 mmol) in Tetrahydrofuran (0.500 mL)and Methanol (0.500 mL). The mixture was stirred at room temperature.After 1 hour, the solvent was concentrated under reduced pressure. Theresidue was dissolved in methylene chloride and treated with 1.00 M ofHydrogen chloride in water (1.00 mL). The organic phases were dried withmagnesium sulfate, filtered and concentrated. Purification bypreparative HPLC gave the product in 37.0 mg yield (39%) as bis-TFAsalt. ESI-MS (M+H+): 465.3; 1H NMR (400 MHz, METHANOL-d4) Shift 8.16 (d,J=9.29 Hz, 1H), 7.83 (s, 1H), 7.58 (dd, J=2.51, 9.29 Hz, 1H), 7.39 (br.s., 1H), 4.90 (s, 2H), 4.35-4.44 (m, 1H), 3.83 (t, J=7.78 Hz, 1H), 2.29(d, J=10.79 Hz, 2H), 1.89-2.00 (m, 2H), 1.42-1.56 (m, 2H), 1.08-1.34 (m,3H), 0.94 (s, 9H). 1.6 TFA per molecule.

Example 1693-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-amino}-propionicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid (Example 168) using the appropriate amine. ESI-MS (M+H+): 453.2; 1HNMR (400 MHz, METHANOL-d4) Shift 8.15 (d, J=9.29 Hz, 1H), 7.85 (s, 1H),7.56 (dd, J=2.26, 9.29 Hz, 1H), 7.38 (br. s., 1H), 4.65 (s, 2H),4.28-4.45 (m, 1H), 3.48 (t, J=6.65 Hz, 2H), 2.88 (t, J=6.78 Hz, 2H),2.27 (d, J=10.79 Hz, 2H), 1.74-2.03 (m, 2H), 1.38-1.54 (m, 2H),1.18-1.32 (m, 2H), 1.04-1.18 (m, 1H), 0.79-0.94 (m, 9H), 1.6 TFA permolecule.

Example 1701-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid (Example 168) using the appropriate amine. ESI-MS (M+H+): 479.2; 1HNMR (400 MHz, METHANOL-d4) Shift 8.17 (d, J=9.29 Hz, 1H), 7.85 (s, 1H),7.58 (dd, J=2.38, 9.41 Hz, 1H), 7.39 (br. s., 1H), 4.85 (br. s., 2H),4.32-4.44 (m, 1H), 3.39-3.53 (m, 1H), 2.51 (br. s., 1H), 2.41 (br. s.,1H), 2.27 (d, J=10.79 Hz, 2H), 1.86-1.99 (m, 2H), 1.34-1.55 (m, 2H),1.19-1.34 (m, 2H), 1.03-1.19 (m, 1H), 0.91 (s, 9H). 1.3 TFA permolecule.

Example 171 4-Bromo-2-methyl-quinolin-6-ol

Synthesized as per 2-Methyl-4-trifluoromethyl-quinolin-6-ol using4-Bromo-6-methoxy-2-methyl-quinoline as starting material. ESI-MS(M+H+): 238.00/240.00.

Example 1724-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-2-methyl-quinoline

Synthesized as per6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinolineusing 4-Bromo-2-methyl-quinolin-6-ol as starting material. ESI-MS(M+H+): 378.1.

Example 1734-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde

To a suspension of Selenium dioxide (0.333 g, 3.00 mmol) in 1,4-Dioxane(8.0 mL) was added a solution of4-Bromo-6-(4-tert-butyl-cyclohexyloxy)-2-methyl-quinoline (0.469 g, 1.25mmol) in 1,4-Dioxane (4.0 mL). The mixture was sealed and was heated at50° C. in an oil bath. After 4 d, the reaction was filtered throughCelite and washed with dioxane. The solvent was evaporated and theresidue was purified on silica gel column using 0-25% ethyl acetate inhexanes as eluent. Isolated was the product (Rf=0.68 in 3:1hexanes/ethyl acetate) in 362 mg yield, 74%. ESI(M+H+): 390.10/392.10.

Example 1741-[4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester using4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde asstarting material. ESI-MS (M+H+): 489.20/491.20.

Example 1751-[6-trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester

A mixture of1-[4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester (0.100 g, 0.204 mmol), methylboronic acid (39 mg, 0.65mmol). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (17 mg, 0.021 mmol), 2 M of Potassiumcarbonate in Water (0.306 mL, 0.613 mmol) and N,N-Dimethylformamide (2.5mL) was added to a 40 mL vial equipped with a magnetic stir bar. Thevial was degassed by stirring under a flow of Ar. The reaction mixturewas stirred at 60° C. under Ar for 3 d. The reaction was cooled, dilutedwith water and extracted with ethyl acetate. The organics were washedwith saturated sodium chloride, dried with sodium sulfate, filtered andevaporated. The residue was purified by silica gel chromatography using0-10% methanol in methylene chloride as eluent (Rf=0.44 in 10%methanol/methylene chloride). Appropriate fractions were combined andevaporated. The product was further purified by preparative HPLC to givethe product in 33 mg yield (25%) as bis-TFA salt. ESI-MS (M+H+): 425.30.

Example 1761-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester as starting material. ESI-MS (M+H+): 411.30; 1H NMR(400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.29 Hz, 1H), 7.41 (dd, J=2.64,9.16 Hz, 1H), 7.36 (d, J=2.51 Hz, 1H), 7.27 (s, 1H), 4.73 (s, 2H),4.45-4.59 (m, 4H), 4.36-4.45 (m, 1H), 3.71-3.86 (m, 1H, 2.69 (s, 3H),2.28 (d, J=11.29 Hz, 2H), 1.92 (d, J=10.79 Hz, 2H), 1.37-1.52 (m, 2H),1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).

Example 1771-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using the appropriate amine. ESI-MS (M+H+): 425.3; 1H NMR (400 MHz,METHANOL-d4) Shift 8.00 (d, J=9.29 Hz, 1H), 7.43 (dd, J=2.51, 9.29 Hz,1H), 7.38 (d, J=2.51 Hz, 1H), 7.32 (s, 1H), 4.63-4.76 (m, 2H), 4.36-4.49(m, 1H), 3.68-3.90 (m, 2H), 3.54-3.68 (m, 2H), 3.37-3.51 (m, 1H), 2.71(s, 3H), 2.45-2.57 (m, 1H), 2.34-2.45 (m, 1H), 2.29 (d, J=10.54 Hz, 2H),1.87-1.98 (m, 2H), 1.37-1.53 (m, 2H), 1.20-1.37 (m, 2H), 1.07-1.20 (m,1H), 0.92 (s, 9H).

Example 1783-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-amino}-propionicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using the appropriate amine. ESI-MS (M+H+): 399.3; 1H NMR (300 MHz,METHANOL-d4) Shift 7.88 (d, J=9.06 Hz, 1H), 7.26-7.35 (m, 2H), 7.21 (s,1H), 4.40 (s, 2H), 4.27-4.38 (m, 1H), 3.31-3.38 (m, 2H), 2.77 (t, J=6.61Hz, 2H), 2.61 (s, 3H), 2.19 (d, J=9.44 Hz, 2H), 1.77-1.89 (m, 2H),1.28-1.43 (m, 2H), 1.10-1.26 (m, 2H), 0.97-1.10 (m, 1H), 0.83 (s,9H).

Example 1791-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester

1-[4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester (0.100 g, 0.000204 mol), cyclopropyl trifluoroboratepotassium salt (0.050 g, 0.00034 mol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.019 g, 0.000023 mol), Cesium Carbonate(0.215 g, 0.000660 mol), Tetrahydrofuran (2.50 mL) and Water (0.25 mL)were added to a 40 mL vial equipped with a magnetic stir bar. The vialwas degassed by stirring under a flow of Ar. The reaction was stirredunder Ar for 3 d at 80° C. The reaction was cooled, diluted with waterand extracted with ethyl acetate. The organics were washed withsaturated sodium chloride, dried with sodium sulfate, filtered andevaporated. The residue was purified by silica gel chromatography using0-10% methanol in DCM as eluent (Rf=0.44 in 10% methanol/DCM). Theproduct was further purified by preparative HPLC. Appropriate fractionswere combined to give the product in 76 mg yield (55%) as bis-TFA salt.ESI-MS (M+H+): 451.30.

Example 1801-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester as starting material. ESI-MS (M+H+): 437.3; 1H NMR(400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.04 Hz, 1H), 7.70 (d, J=2.76Hz, 1H), 7.41 (dd, J=2.64. 9.16 Hz, 3H), 7.08 (s, 1H), 4.71 (s, 2H),4.36-4.59 (m, 5H), 3.70-3.86 (m, 1H), 2.38-2.51 (m, 1H), 2.30 (d,J=10.54 Hz, 2H), 1.85-1.99 (m, 2H), 1.37-1.53 (m, 2H), 1.19-1.34 (m,4H), 1.05-1.19 (m, 1H), 0.92 (s, 9H), 0.81-0.89 (m, 2H).

Example 1811-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using the appropriate intermediate available from the synthesis of1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid). ESI-MS (M+H+): 451.3; 1H NMR (400 MHz, METHANOL-d4) Shift 7.99(d, J=9.29 Hz, 1H), 7.70 (d, J=2.51 Hz, 1H), 7.42 (dd, J=2.64. 9.16 Hz,1H), 7.13 (s, 1H), 4.60-4.72 (m, 2H), 4.35-4.49 (m, 1H), 3.81 (dd,J=6.53, 12.05 Hz, 1H), 3.72 (dd, J=8.66, 11.92 Hz, 1H), 3.50-3.66 (m,2H), 3.37-3.49 (m, 1H), 2.42-2.55 (m, 2H), 2.38 (td, J=6.96, 13.68 Hz,1H), 2.29 (d, J=10.29 Hz, 2H), 1.85-1.98 (m, 2H), 1.36-1.52 (m, 2H),1.18- 1.34 (m, 4H), 1.03-1.18 (m, 1H), 0.91 (s, 9H), 0.79-0.89 (m, 2H).

Example 1823-{[6-trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-amino}-propionicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using the appropriate intermediate available from the synthesis of3-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-amino}-propionicacid.) ESI-MS (M+H+): 425.3; 1H NMR (400 MHz, METHANOL-d4) Shift 8.00(d, J=9.29 Hz, 1H), 7.72 (d, J=2.51 Hz, 1H), 7.43 (dd, J=2.64, 9.16 Hz,1H), 7.14 (s, 1H), 4.50 (s, 2H), 4.40-4.49 (m, 1H), 3.44 (t, J=6.78 Hz,2H), 2.87 (t, J=6.65 Hz, 2H), 2.44-2.54 (m, 1H), 2.32 (d, J=11.04 Hz,2H), 1.91-1.99 (m, 2H), 1.42-1.54 (m, 2H), 1.21-1.36 (m, 4H), 1.07-1.21(m, 1H), 0.94 (s, 9H), 0.84-0.92 (m, 2H).

Example 183 6-Bromo-2-(4-tert-butyl-cyclohexyloxy)-quinoline

Synthesized as per6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinolineusing 6-Bromo-quinolin-2-ol as starting material. Alkylation wasconfirmed to be on the oxygen by 2D NMR (HMQC) of the subsequentintermediate. ESI-MS (M+H+): 362.1/364.10).

Example 1842-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline-6-carbaldehyde

To 6-Bromo-2-(trans-4-tert-butyl-cyclohexyloxy)-quinoline (1.0933 g,3.0176 mmol) in Tetrahydrofuran (24 mL) was added 1.6 M ofn-Butyllithium in hexane (5.6 mL, 9.0 mmol) at −78° C. and the reactionwas stirred for 15 min, N,N-Dimethylformamide (1.2 mL) was added and thereaction was stirred for 30 minutes. 1 M HCl was added and the reactionallowed to warm to RT. Saturated sodium bicarbonate solution was addedand the mixture extracted with ethyl acetate. The organic layer waswashed with saturated sodium chloride, dried with sodium sulfate,filtered and evaporated. The residue was purified by silica gelchromatography using hexanes/ethyl acetate (0-50%) as eluent to giveproduct in 603 mg yield (64%), ESI-MS (M+H+): 312.20.

Example 1851-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylicacid methyl ester

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester using2-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline-6-carbaldehyde asstarting material ESI-MS (M+H+): 411.30.

Example 1861-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylicacid

Synthesized as per1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid using1-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylicacid methyl ester as starting material. ESI-MS (M+H+): 397.39; 1H NMR(400 MHz, METHANOL-d4) Shift 8.15 (d, J=8.78 Hz, 1H), 7.89-7.94 (m, 1H),7.86 (d, J=8.78 Hz, 1H), 7.67 (dd, J=1.88, 8.66 Hz, 1H), 6.96 (d, J=8.78Hz, 1H), 5.10-5.22 (m, 1H), 4.55 (s, 2H), 4.20-4.47 (m, 4H), 3.71 (quin,J=8.28 Hz, 1H), 2.28 (d, J=9.54 Hz, 2M), 1.92 (d, J=14.31 Hz, 2H),1.36-1.52 (m, 2H), 1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).

Example 1871-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-pyrrolidine-3-carboxylicacid

Synthesized as per1-[2-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-6-ylmethyl]-azetidine-3-carboxylicacid using the appropriate amine. ESI-MS (M+H+): 411.41; 1H NMR (400MHz, METHANOL-d4) Shift 8.14 (d, J=8.78 Hz, 1H), 7.90-7.98 (m, 1H), 7.86(d, J=8.53 Hz, 1H), 7.72 (dd, J=1.88, 8.66 Hz, 1H), 6.95 (d, J=8.78 Hz,1H), 5.04-5.27 (m, 1H), 4.54 (br. s., 2H), 3.31-4.11 (m, 5H), 2.15-2.61(m, 4H), 1.90 (d, J=13.05 Hz, 2H), 1.35-1.52 (m, 2H), 1.17-1.35 (m, 2H),1.03-1.17 (m, 1H), 0.91 (s, 9H).

Example 188 6-(trans-4-tert-butylcyclohexyloxy)-2-methylquinoline

To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), cis4-tert-Butyl-cyclohexanol (4.86 g, 0.0311 mol) and triphenylphosphine(9.53 g, 0.0363 mol; Supplier=Aldrich) in tetrahydrofuran (100 mL, 1mol; Supplier=Acros), cooled in an ice bath, was added diisopropylazodicarboxylate (7.61 mL, 0.0363 mol; Supplier=Acros) inTetrahydrofuran (10 mL, 0.1 mol; Supplier=Acros), The reaction mixturewas stirred for 72 h allowing to reach room temperature. The solvent wasremoved under reduced pressure and the residue was taken up in methylenechloride, adsorbed onto silica gel and purified by flash chromatography(0-30% ethyl acetate in hexanes) to give the title compound in 56%yield. ESI-MS (M+H+): 298.3.

Example 189 6-(trans-4-tert-butylcyclohexyloxy)quinoline-2-carbaldehyde

Di-tert-butyl peroxide (1.93 mL, 10.5 mmol) was added to a suspension ofSelenium dioxide (2.68 g, 24.1 mmol) in 1.4-Dioxane (24.00 mL, 307.5mmol). The mixture was stirred for 30 minutes, then6(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-quinoline (3.12 g, 10.5mmol) was added as a solution in 1,4-Dioxane and the mixture was heatedovernight at 50° C. The reaction mixture was then cooled to roomtemperature, diluted in chloroform and filtered through a pad of ceiite.The filtrate was washed with water. The layers were separated and thecombined organic phase was dried over MgSO₄, filtered, concentratedunder reduced pressure, adsorbed onto silica gel and purified by flashchromatography (0-30% EtOAc in hexanes) to give the title compound as apale yellow solid in 20% yield. ESI-MS (M+H+): 312.27.

Example 190 tert-butyl3-((6-(trans-4-tert-butylcyclohexyloxy)quinolin-2yl)methylamino)propanoate

A solution of triethylamine (0.07356 mL, 0.5278 mmol),6-(trans-4-tert-Butyl-cyclohexyloxy)-quinoline-2-carbaldehyde (0.1259 g,0.4043 mmol) and β-alanine t-butyl ester HCl salt (0.08813 g, 0.4851mmol) in 1,2-Dichloroethane (5.00 mL, 63.5 mmol) was stirred for 1 hourat room temperature. Sodium triacetoxyborohydride (0.1714 g, 0.8086mmol) was then added and the mixture was stirred overnight. The reactionwas diluted in methylene chloride and washed with saturated aq. sodiumbicarbonate. The organic phase was dried over MgSO₄, filtered, adsorbedonto silica gel and purified by flash chromatography (0-5% MeOH inmethylene chloride) to give the title compound in 66% yield. ESI-MS(M+H+): 441.50.

Example 1913-((6-((trans-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoicacid

2 M of Lithium hydroxide, monohydrate in Water (1.00 mL, 2.00 mmol) wasadded to a solution of3-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-propionicacid tert-butyl ester (0.2416 g, 0.5483 mmol) in Tetrahydrofuran (1.00mL, 12.3 mmol) and Methanol (1.00 mL, 24.7 mmol). The mixture wasstirred overnight at room temperature. The solvent was removed underreduced pressure and the residue was dissolved in methylene chloride andwashed with water. The organic phase was concentrated under reducedpressure to give the title compound. ESI-MS (M+H+): 385.42. 1H NMR (400MHz, MeOD) Shift 8.16 (d, J=8.53 Hz, 1H), 7.86 (d, J=9.04 Hz, 1H), 7.51(d, J=8.53 Hz, 1H), 7.31 (dd, J=2.76, 9.04 Hz, 1H), 7.24 (d, J=2.51 Hz,1H), 4.29-4.39 (m, 1H), 3.99 (s, 2H), 2.86 (t, J=6.90 Hz, 2H), 2.42 (t,J=6.90 Hz, 2H), 2.22-2.30 (m, 2H), 1.85-1.93 (m, 2H), 1.34-1.47 (m, 2H),1.19-1.31 (m, 2H), 1.04-1.15 (m, 1H), 0.89 (s, 9H)

The following compounds were synthesized as3-(6-(trans-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoicacid using the appropriate cyclohexanols and aminoesters:

Example 192 1-[6-(trans4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 411.64; 1H NMR (400 MHz, METHANOL-d4) Shift 8.56 (d,J=8.53 Hz, 1H), 8.11 (d, J=9.29 Hz, 1H), 7.75 (d, J=8.53 Hz, 1H), 7.55(dd, J=2.76, 9.29 Hz, 1H), 7.48 (d, J=2.76 Hz, 1H), 4.90 (d, J=2.51 Hz,2H), 4.40-4.51 (m, 1H), 3.78-3.93 (m, 2H), 3.60-3.74 (m, 2H), 3.45-3.55(m, 1H), 2.54 (dt, J=6.96, 8.91 Hz, 1H), 2.37-2.47 (m, 1H), 2.29 (d,J=2.76 Hz, 2H), 1.89-1.98 (m, 2H), 1.41-1.53 (m, 2H), 1.24-1.37 (m, 2H),1.11-1.20 (m, 1H), 0.92 (s, 9H)

Example 193 1-[6-(trans4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid

ESI-MS (M+H+): 397.44; 1H NMR (400 MHz, MeOD) Shift 8.26 (d, J=8.03 Hz,1H), 7.97 (d, J=9.04 Hz, 1H), 7.37-7.42 (m, 2H), 7.30-7.34 (m, 1H), 4.79(s, 2H), 4.48-4.59 (m, 4H), 4.34-4.44 (m, 1H), 2.66 (s, 1H), 2.25-2.33(m, J=11.55 Hz, 2H), 1.89-1.97 (m, 2H), 1.38-1.51 (m, 2H), 1.22-1.35 (m,2H), 1.07-1.19 (m, J=11.80 Hz, 1H), 0.93 (s, 9H)

Example 194 1-[6-(trans4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

Enantiomer 1, separated by chiral HPLC. ESI-MS (M+H+): 411.35; 1H NMR(400 MHz, DMSO-d6) Shift 8.16 (d, J=8.28 Hz, 1H), 7.83 (s, 1H), 7.50 (d,J=8.28 Hz, 1H), 7.38 (s, 1H), 7.31 (dd, J=2.76, 9.04 Hz, 1H), 4.31-4.42(m, 1H), 3.77 (d, J=5.02 Hz, 2H), 2.80-2.90 (m, 1H), 2.69-2.77 (m, 1H),2.52-2.67 (m, 4H), 2.15-2.24 (m, 2H), 1.88-2.00 (m, 2H), 1.76-1.85 (m,2H), 1.28-1.40 (m, 2H), 1.14-1.27 (m, 2H), 0.87 (s, 9H)

Example 195 1-[6-(trans4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

Enantiomer 2, separated by chiral HPLC. ESI-MS (M+H+): 411.36; 1H NMR(400 MHz, DMSO-d6) Shift 8.16 (d, J=8.53 Hz, 1H), 7.82 (d, J=9.04 Hz,1H), 7.50 (d, J=8.53 Hz, 1H), 7.38 (s, 1H), 7.28-7.34 (m, 1H), 4.32-4.42(m, 1H), 3.78 (d, J=5.02 Hz, 2H), 2.83-2.92 (m, 1H), 2.71-2.77 (m, 1H),2.51-2.68 (m, 4H), 2.17-2.24 (m, 2H), 1.89-2.00 (m, 2H), 1.77-1.85 (m,2H), 1.29-1.41 (m, 2H), 1.14-1.27 (m, 2H), 0.87 (s, 9H)

Example 196 1-[6-(trans4-Cyclopentyl-cyclohexyloxy)-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 423.33; 1H NMR (400 MHz, MeOD) Shift 8.29 (d, J=8.28 Hz,1H), 8.01 (d, J=9.29 Hz, 1H), 7.40-7.48 (m, 2H), 7.34 (d, J=2.76 Hz,1H), 4.77 (d, J=6.27 Hz, 2H), 4.38-4.49 (m, 1H), 3.79 (d, J=2.51 Hz,2H), 3.65 (br. s., 2H), 3.43-3.52 (m, 1H), 2.52 (dq, J=7.02, 8.82 Hz,1H), 2.43 (dt, J=6.87, 13.62 Hz, 1H), 2.20-2.29 (m, 2H), 1.93-2.02 (m,2H), 1.78-1.89 (m, 2H), 1.41-1.71 (m, 7H), 1.11-1.30 (m, 5H)

Example 197 1-[6-(trans4-Cyclopentyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3-carboxylicacid

ESI-MS (M+H+): 409.33; 1H NMR (400 MHz, MeOD) Shift 8.26 (d, J=8.53 Hz,1H), 7.98 (d, J=9.29 Hz, 1H), 7.41-7.43 (m, 1H), 7.38-7.41 (m, 1H), 7.32(d, J=2.51 Hz, 1H), 4.80 (s, 2H), 4.48-4.61 (m, 4H), 4.38-4.47 (m, 1H),3.81 (quin, J=8.35 Hz, 1H), 2.20-2.28 (m, 2H), 1.93-2.01 (m, 2H),1.79-1.88 (m, 2H), 1.40-1.71 (m, 7H), 1.12-1.29 (m, 5H)

Example 198 3-{[6-(trans4-Cyclopentyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-propionic acid

ESI-MS (M+H+): 397.01; 1H NMR (400 MHz, MeOD) Shift 8.27 (d, J=8.28 Hz,1H), 7.99 (d, J=9.29 Hz, 1H), 7.44 (d, J=8.53 Hz, 1H), 7.41 (dd, J=2.76,9.29 Hz, 1H), 7.32 (d, J=2.76 Hz, 1H), 4.56 (s, 2H), 4.38-4.47 (m, 1H),3.47 (t, J=6.65 Hz, 2H), 2.88 (t, J=6.78 Hz, 2H), 2.20-2.28 (m, 2H),1.93-2.00 (m, 2H), 1.78-1.88 (m, 2H), 1.40-1.71 (m, 8H), 1.11-1.29 (m,5H)

Example 199 1-{6-[trans4-(1,1-Dimethyl-propyl)-cyclohexyloxyl]-quinolin-2-ylmethyl}-pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 425.31; 1H NMR (400 MHz, MeOD) Shift 8.29 (d, J=8.28 Hz,1H), 8.01 (d, J=9.29 Hz, 1H), 7.40-7.47 (m, 2H), 7.34 (d, J=2.76 Hz,1H), 4.77 (d, J=6.02 Hz, 2H), 4.36-4.46 (m, 1H), 3.73-3.93 (m, 2H), 3.65(br. s., 2H), 3.42-3.53 (m, 1H), 2.36-2.59 (m, 2H), 2.26-2.34 (m, 2H),1.83-1.93 (m, 2H), 1.40-1.52 (m, 2H), 1.23-1.39 (m, 5H), 0.82-0.91 (m,9H)

Example 200 1-{6-[trans4-(1,1-Dimethyl-propyl)-cyclohexyloxy]-quinolin-2-ylmethyl}-azetidine-3-carboxylicacid

ESI-MS (M+H+): 411.32; 1H NMR (400 MHz, MeOD) Shift 8.26 (d, J=8.28 Hz,1H), 7.97 (d, J=9.29 Hz, 1H), 7.41-7.43 (m, 1H), 7.37-7.40 (m, 1H), 7.32(d, J=2.51 Hz, 1H), 4.80 (s, 2H), 4.48-4.60 (m, 4H), 4.35-4.44 (m, 1H),3.81 (quin, J=8.35 Hz, 1H), 2.25-2.34 (m, 2H), 1.84-1.92 (m, 2H),1.23-1.51 (m, 7H), 0.82-0.91 (m, 9H)

Example 201 3-({6-[trans4-(1,1-Dimethyl-propyl)-cyclohexyloxy]-quinolin-2-ylmethyl}-amino)-propionicacid

ESI-MS (M+H+): 399.32; 1H NMR (400 MHz, MeOD) Shift 8.27 (d, J=8.28 Hz,1H), 7.98 (d, J=9.29 Hz, 1H), 7.44 (d, J=8.53 Hz, 1H), 7.40 (dd, J=2.76,9.29 Hz, 1H), 7.32 (d, J=2.76 Hz, 1H), 4.56 (s, 2H), 4.35-4.44 (m, 1H),3.46 (t, J=6.78 Hz, 2H), 2.88 (t, J=6.78 Hz, 2H), 2.26-2.33 (m, 2H),1.84-1.91 (m, 2H), 1.38-1.51 (m, 2H), 1.23-1.38 (m, 5H), 0.82-0.90 (m,10H)

Example 202 (1S,2R)-2-{[6-(trans4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-cyclohexanecarboxylicacid

ESI-MS (M+H+): 439.35; 1H NMR (400 MHz, MeOD) Shift 8.28 (d, J=8.28 Hz,1H), 7.99 (d, J=9.04 Hz, 1H), 7.46 (d, J=8.28 Hz, 1H), 7.42 (dd, J=2.76,9.29 Hz, 1H), 7.34 (d, J=2.76 Hz, 1H), 4.60 (b, 2H), 4.36-4.45 (m, 1H),3.50 (dt, 1H), 2.04-2.35 (m, 2H), 1.89-1.99 (m, J=12.05 Hz, 3H),1.59-1.69 (m, 2H), 1.40-1.53 (m, 3H), 1.14-1.36 (m, 3H), 0.93 (s, 9H)

Example 203(1S,2S)-2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-cyclohexanecarboxylicacid

ESI-MS (M+H+): 439.36; 1H NMR (400 MHz, MeOD) Shift 8.29 (d, J=8.28 Hz,1H), 7.98 (d, J=9.04 Hz, 1H), 7.47 (d, J=8.53 Hz, 1H), 7.41 (dd, J=2.76,9.29 Hz, 1H), 7.34 (d, J=2.76 Hz, 1H), 4.69 (d, J=15.31 Hz, 1H), 4.56(d, J=15.31 Hz, 1H), 4.36-4.46 (m, 1H), 3.48-3.60 (m, 1H), 2.65-2.75 (m,1H), 2.26-2.39 (m, 4H), 1.90-1.99 (m, 3H), 1.86 (d, 1H), 1.36-1.60 (m,5H), 1.24-1.36 (m, 2H), 1.17 (dt, 1H), 0.94 (s, 9H)

Example 204(1S,2R)-2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-cyclopentanecarboxylicacid

ESI-MS (M+H+): 425.52; 1H NMR (400 MHz, MeOD) Shift 8.26-8.31 (m, 1H),7.96-8.02 (m, 1H), 7.43-7.48 (m, 1H), 7.41 (dd, J=2.76, 9.29 Hz, 1H),7.34 (d, J=2.76 Hz, 1H), 4.51-4.66 (m, 2H), 4.36-4.46 (m, 1H), 3.82-4.13(m, 1H), 2.22-2.34 (m, 3H), 2.10-2.21 (m, 1H), 1.89-2.06 (m, 4H),1.74-1.85 (m, 1H), 1.39-1.52 (m, 2H), 1.23-1.36 (m, 2H), 1.11-1.20 (m,1H), 0.95 (s, 9H)

Example 205 7-(trans 4-tert-butylcyclohexyloxy)-3-methylisoquinoline

Triphenylphosphine (5.14 g, 19.6 mmol) was added to a solution of3-Methyl-isoquinolin-7-ol (2.08 g, 13.1 mmol) andcis-4-tert-butylcyclohexanol (3.06 g, 19.6 mmol) in Toluene (60 mL, 600mmol). The mixture was stirred for 15 minutes then Diisopropylazodicarboxylate (3.86 mL, 19.6 mmol) was added. The mixture was thenstirred at room temperature overnight. The solvent was removed undervacuum. The crude product was dissolved in methylene chloride, adsorbedonto silica gel and purified by flash chromatography (0-30% EtOAc inhexanes) to give the title compound in 52% yield. ESI-MS (M+H+): 298.46.

Example 2067-(trans-4-tert-butylcyclohexyloxy)isoquinoline-3-carbaldehyde

Selenium dioxide (2.25 g, 20.3 mmol) was added to a solution of7-(trans-4-tert-Butyl-cyclohexyloxy)-3-methyl-isoquinoline (2.01 g, 6.76mmol) in Diphenyl ether (50 mL, 300 mmol) and the mixture was heated at200° C. in a sealed tube for 4 hours. The reaction was then cooled toroom temperature. Silica gel was added and the flask was placed in acold water bath to solidify the diphenylether solvent. This solidmixture containing the crude product was purified by flashchormatography (0-30% EtOAc in hexanes) to give the title compound in50% yield. ESI-MS (M+H+): 312.27

Example 207 tert-butyl3-((7-(trans-4-tert-butylcyclohexyloxy)isoquinolin-3-yl)methylamino)propanoate

Triethylamine (0.07356 mL, 0.5278 mmol) was added to a solution of7-(trans-4-tert-Butyl-cyclohexyloxy)-isoquinoline-3-carbaldehyde (0.1174g, 0.3770 mmol) and 3-Amino-propionic acid ethyl ester HCl salt;(0.08107 g, 0.5278 mmol) in 1,2-Dichloroethane (5.00 mL, 63.5 mmol) andthe mixture was stirred for 1 hour at room temperature. Sodiumtriacetoxyborohydride (0.1118 g, 0.5278 mmol) was then added and themixture was stirred for 2 hours. The reaction was diluted in methylenechloride and washed with saturated aq. sodium bicarbonate. The organicphase was dried over MgSO₄, filtered, adsorbed onto silica gel andpurified by flash chromatography (0-5% MeOH in methylene chloride) togive the title compound in 97% yield. ESI-MS (M+H+): 413.35.

Example 2083-((7-(trans-4-tert-butylcyclohexyloxy)isoquinolin-3-yl)methylamino)propanoicacid

2 M of Lithium hydroxide, monohydrate in water (1.00 mL, 2.00 mmol) wasadded to a solution of3-{[7-(trans-4-tert-butyl-cyclohexyloxy)-isoquinoline-3-ylmethyl]-amino}-propionic acid ethyl ester (0.1505 g, 0.3648 mmol)in Tetrahydrofuran (1.00 mL, 12.3 mmol) and Methanol (1.00 mL, 24.7mmol). The mixture was stirred for 2 hours. The solvent was thenevaporated under reduced pressure. The resulting residue was dissolvedin methylene chloride and washed with a solution of 1 M of Hydrogenchloride in Water (1.999 mL, 1.999 mmol). The organic layer was thenconcentrated to dryness under reduced pressure. The crude product wasdissolved in DMSO and purified by HPLC to give the title compound as abis-TFA salt, ESI-MS (M+H+): 385.51 [M+1]. 1H NMR (400 MHz, MeOD) Shift9.22 (s, 1H), 7.86 (d, J=9.04 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J=2.51 Hz,1H), 7.43 (dd, J=2.51, 9.04 Hz, 1H), 4.46 (s, 2H), 4.40-4.46 (m, 1H),3.37 (t, J=6.65 Hz, 2H), 2.81 (t, J=6.78 Hz, 2H), 2.25-2.34 (m, 2H),1.89-1.98 (m, 2H), 1.40-1.52 (m, 2H), 1.24-1.37 (m, 2H), 1.10-1.20 (m,1H), 0.90-0.95 (m, 9H)

The following compounds were synthesized as3-((7-(trans-4-tert-butylcyclohexyloxy)isoquinoline-3-yl)methylamino)propanoic acid using the appropriatecyclohexanols and aminoesters:

Example 2091-[7-(trans-4-tert-Butyl-cyclohexyloxy)-isoquinolin-3-ylmethyl]-pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 411.33; 1H NMR (400 MHz, MeOD) Shift 9.23 (s, 1H), 7.87(d, J=9.04 Hz, 1H), 7.83 (s, 1H), 7.51 (d, J=2.26 Hz, 1H), 7.44 (dd,J=2.51, 8.78 Hz, 1H), 4.56-4.68 (m, 2H), 4.39-4.49 (m, 1H), 3.61-3.78(m, 2H), 3.52 (t, J=7.28 Hz, 2H), 3.37-3.47 (m, 1H), 2.33-2.52 (m, 2H),2.25-2.33 (m, 2H), 1.88-1.97 (m, 2H), 1.39-1.51 (m, 2H), 1.23-1.35 (m,2H), 1.09-1.18 (m, 1H), 0.91 (s, 9H)

Example 2101-[7-(trans-4-tert-Butyl-cyclohexyloxy)-isoquinolin-3-ylmethyl]-azetidine-3-carboxylicacid

ESI-MS (M+H+): 397.32; 1H NMR (400 MHz, MeOD) Shift 9.20 (s, 1H), 7.87(d, J=9.04 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=2.51 Hz, 1H), 7.44 (dd,J=2.51, 9.04 Hz, 1H), 4.65 (s, 2H), 4.39-4.50 (m, 5H), 3.70-3.81 (m,1H), 2.26-2.35 (m, 2H), 1.90-1.99 (m, 2H), 1.41-1.53 (m, 2H), 1.30 (qd,2H), 1.09-1.21 (m, J=2.54, 2.54, 11.48 Hz, 1H), 0.93 (s, 9H)

Example 2111-[7-(trans-4-Cyclopentyl-cyclohexyloxy)isoquinolin-3-ylmethyl]-pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 423.28; 1H NMR (400 MHz, MeOD) Shift 9.24 (s, 1H), 7.88(d, J=9.04 Hz, 1H), 7.84 (s, 1H), 7.51 (d, J=2.26 Hz, 1H), 7.45 (dd,J=2.38, 8.91 Hz, 1H), 4.59-4.69 (m, 2H), 4.43-4.54 (m, 1H), 3.63-3.79(m, 2H), 3.53 (t, J=7.28 Hz, 2H), 3.38-3.48 (m, 1H), 2.32-2.54 (m, 2H),2.21-2.29 (m, 2H), 1.93-2.02 (m, 2H), 1.79-1.88 (m, 2H), 1.42-1.71 (m,6H), 1.11-1.31 (m, 6H)

Example 2121-[7-(trans-4-Cyclopentyl-cyclohexyloxy)-isoquinolin-3-ylmethyl]-azetidine-3-carboxylicacid

ESI-MS (M+H+): 409.29; 1H NMR (400 MHz, MeOD) Shift 9.20 (s, 1H), 7.87(d, J=9.04 Hz, 1H), 7.80 (s, 1H), 7.49 (d, J=2.26 Hz, 1H), 7.44 (dd,J=2.38, 8.91 Hz, 1H), 4.65 (s, 2H), 4.39-4.52 (m, 5H), 3.70-3.81 (m,1H), 2.25 (dd, J=3.64, 13.18 Hz, 2H), 1.93-2.01 (m, 2H), 1.78-1.88 (m,2H), 1.41-1.71 (m, 7H), 1.11-1.31 (m, 5H)

Example 2133-{[7-(trans-4-Cyclopentyl-cyclohexyloxy)-isoquinolin-3-ylmethyl]-amino}-propionicacid

ESI-MS (M+H+): 397.29; 1H NMR (400 MHz, MeOD) Shift 9.23 (s, 1H), 7.87(d, J=8.78 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J=2.26 Hz, 1H), 7.44 (dd,J=2.51, 9.04 Hz, 1H), 4.43-4.53 (m, 3H), 3.35-3.41 (m, 2H), 2.82 (t,J=6.65 Hz, 2H), 2.21-2.30 (m, 2H), 1.93-2.02 (m, 2H), 1.80-1.80 (m, 0H),1.79-1.88 (m, J=6.02 Hz, 2H), 1.41-1.71 (m, 7H), 1.12- 1.30 (m, 5H)

Example 2141-(7-(trans-4-tert-pentylcyclohexyloxy)isoquinolin-3-yl)methyl)pyrrolidine-3-carboxylicacid

ESI-MS (M+H+): 425.31; 1H NMR (400 MHz, MeOD) Shift 9.23 (s, 1H), 7.86(d, J=9.04 Hz, 1H), 7.83 (s, 1H), 7.50 (d, J=2.26 Hz, 1H), 7.43 (dd,J=2.38, 8.91 Hz, 1H), 4.57-4.67 (m, 2H), 4.38-4.49 (m, 1H), 3.61-3.78(m, 2H), 3.52 (t, J=7.28 Hz, 2H), 3.37-3.46 (m, 1H), 2.25-2.52 (m, 4H),1.83-1.91 (m, 2H), 1.38-1.51 (m, 2H), 1.20-1.38 (m, 5H), 0.81-0.89 (m,9H)

Example 2151-(7-(trans-4-tert-pentylcyclohexyloxy)isoquinolin-3-yl)methyl)-azetidine-3-carboxylicacid

ESI-MS (M+H+): 411.31; 1H NMR (400 MHz, MeOD) Shift 9.20 (s, 1H), 7.86(d, J=9.04 Hz, 1H), 7.80 (s, 1H), 7.49 (d, J=2.26 Hz, 1H), 7.43 (dd,J=2.51, 9.04 Hz, 1H), 4.65 (s, 2H), 4.39-4.49 (m, 5H), 3.70-3.80 (m,3H), 2.26-2.34 (m, J=11.04 Hz, 2H), 1.84-1.92 (m, 2H), 1.39-1.51 (m,2H), 1.21-1.39 (m, 5H), 0.83-0.90 (m, 9H)

Example 2163-((7-(trans-4-tert-pentylcyclohexyloxy)isoquinolin-3-yl)methylamino)propanoicacid

ESI-MS (M+H+): 399.33; 1H NMR (400 MHz, MeOD) Shift 9.22 (s, 1H), 7.86(d, J=8.78 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J=2.51 Hz, 1H), 7.43 (dd,J=2.51, 9.04 Hz, 1H), 4.46 (s, 2H), 4.39-4.45 (m, 1H), 3.37 (t, J=6.65Hz, 2H), 2.81 (t, J=6.65 Hz, 2H), 2.26-2.34 (m, J=2.76, 13.05 Hz, 2H),1.83-1.91 (m, 2H), 1.39-1.51 (m, J=11.63, 11.63, 11.63 Hz, 2H),1.20-1.38 (m, 5H), 0.82-0.90 (m, 9H).

Example 2176-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene

6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene(2.58 g, 6.01 mmol) was dissolved in Tetrahydrofuran (100 mL, 1000 mmol)and cooled to −78° C. in a dry ice/acetone bath. 1.6 M of n-Butyllithiumin Hexane (7.512 mL, 12.02 mmol) was slowly added and the mixture wasstirred for 30 minutes. N,N-Dimethylformamide (1.396 mL, 18.03 mmol) wasthen slowly added and the mixture was allowed to reach room temperature.The reaction mixture was poured into 1N HCl and extracted with ethylacetate. The combined organic phase wash washed with sat. aq. sodiumbicarbonate solution, brine, then dried over MgSO₄, filtered,concentrated and purified by flash chromatography (0-20% EtOAc inhexanes) to give the title compound in 80% yield. ESI-MS (M+H+): 379.41

Example 2182-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalene-2-ylmethyl]-amino}-ethanesulfonicacid

Taurine (0.03737 g, 0.2986 mmol) was added to a solution of6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde(0.1130 g, 0.2986 mmol) in Ethanol (3.00 mL, 51.4 mmol) and the mixturewas refluxed for 1 hour. The mixture was cooled to room temperature andSodium cyanoborohydride (0.02252 g, 0.3583 mmol) was added. The mixturewas then refluxed overnight. The reaction mixture was cooled to roomtemperature, washed with saturated aqueous citric acid solution (4 ml),then concentrated to dryness under reduced pressure. The resulting solidwas washed with water and filtered. The residue was washed with water(10 mL), ether (10 mL) and hexane (10 mL) consecutively, then filtered.The residue was purified by prep HPLC to give the title compound. ESI-MS(M+H+): 488.3; 1H NMR (400 MHz, DMSO-d6) Shift 8.46-8.52 (m, 1H),7.83-7.88 (m, 1H), 7.73-7.80 (m, 2H), 7.35-7.40 (m, 2H), 4.21-4.30 (m,1H), 4.02 (br. s., 2H), 2.88 (t, J=6.78 Hz, 2H), 2.50 (d, J=13.80 Hz,2H), 1.77-1.85 (m, 2H), 1.43-1.52 (m, 2H), 1.00-1.13 (m, 2H), 0.67-0.92(m, 3H), 0.53 (s, 9H).

The following compound was synthesized as2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-ylmethyl]-amino}-ethanesulfonicacid using the appropriate aminosulfone:

Example 219[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-ylmethyl]-(2-methanesulfonyl-ethyl)-amine

ESI-MS (M+H+): 486.52; 1H NMR (400 MHz, MeOD) Shift 8.13 (dd, J=1.88,8.91 Hz, 1H), 8.03 (d, J=9.29 Hz, 1H), 7.83 (d, J=1.51 Hz, 1H), 7.58(dd, J=2.01, 9.04 Hz, 1H), 7.49 (d, J=9.04 Hz, 1H), 4.39-4.49 (m, 1H),3.96 (s, 2H), 3.36 (d, J=7.78 Hz, 2H), 3.13 (t, J=6.27 Hz, 2H), 3.04 (s,3H), 2.17-2.26 (m, 2H), 1.87-1.95 (m, 2H), 1.43-1.56 (m, 2H), 1.06-1.30(m, 3H), 0.90 (s, 9H)

Example 2202-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethanesulfonicacid

A solution of6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.1662g, 0.5354 mmol) and Taurine (0.06700 g, 0.5354 mmol) in anhydrousEthanol (4.00 mL, 68.5 mmol) was refluxed for 2 hours. The mixture wascooled to room temperature and Sodium cyanoborohydride (0.04037 g,0.6425 mmol) was added. The mixture was then refluxed overnight. Thereaction mixture was cooled to room temperature and washed with Sat.aqueous citric acid (4 mL). The mixture was then concentrated to drynessunder reduced pressure. The resulting solid was suspended in water andfiltered. The residue was washed with water, air-dried and purified byprep HPLC to give the title compound. ESI-MS (M+H+): 420.34; 1H NMR (400MHz, DMSO-d6) Shift 8.68 (br. s., 1H), 7.84 (br. s., 1H), 7.73-7.81 (m,2H), 7.45 (dd, J=1.76, 8.53 Hz, 1H), 7.32-7.35 (m, 1H), 7.12 (dd,J=2.51, 8.78 Hz, 1H), 4.29-4.38 (m, 1H), 4.24 (br. s., 2H), 3.13 (d,J=13.80 Hz, 2H), 2.76 (d, J=13.55 Hz, 2H), 2.10-2.18 (m, 2H), 1.72-1.80(m, 2H), 1.23-1.36 (m, 2H), 1.09-1.22 (m, 2H), 0.96-1.06 (m, 1H), 0.81(s, 9H)

The following compounds were synthesized as2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethanesulfonicacid using the appropriate amines:

Example 2213-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-propane-1-sulfonicacid

ESI-MS (M+H+): 434.44; 1H NMR (400 MHz, MeOD) Shift 7.90 (br. s., 1H),7.85 (d, J=8.53 Hz, 1H), 7.81 (d, J=9.04 Hz, 1H), 7.51 (dd, J=1.76, 8.53Hz, 1H), 7.29 (d, J=2.26 Hz, 1H), 7.18 (dd, J=2.51, 9.04 Hz, 1H),4.34-4.43 (m, 1H), 4.33 (s, 2H), 2.96 (t, J=6.65 Hz, 2H), 2.25-2.33 (m,2H), 2.19 (quin, J=6.90 Hz, 2H), 1.89-1.97 (m, 2H), 1.38-1.50 (m, 2H),1.23-1.35 (m, 2H), 1.08-1.19 (m, 1H), 0.92 (s, 9H)

Example 222N-(2-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-ethyl)-4-trifluoromethyl-benzenesulfonamide

ESI-MS (M+H+): 563.50; 1H NMR (400 MHz, DMSO-d6) Shift 7.91-8.00 (m,5H), 7.69-7.75 (m, 3H), 7.62-7.66 (m, 1H), 7.30-7.38 (m, 3H), 7.08-7.13(m, 1H), 4.30-4.40 (m, 1H), 3.70-3.75 (m, 2H), 2.90 (t, J=6.53 Hz, 2H),2.15-2.23 (m, 2H), 1.77-1.85 (m, 2H), 1.28-1.40 (m, 2H), 1.15-1.27 (m,2H), 1.02-1.12 (m, 1H), 0.87 (s, 9H)

Example 2231-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpyrrolidine-3-carboxylicacid

A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(140 mg, 0.46 mmol) and 4-methylpyrrolidine-3-carboxylic acid (60.1 mg,0.465 mmol) in Ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h.The yellow solution was cooled to rt and Sodium cyanoborohydride (35.1mg, 0.558 mmol) was added and was heated to reflux, for 1 h. Aftercooled down to rt, DCM, water and citric acid were added along with somebrine to clear up the layers. Concentration of the cloudy organic layergave a precipitate that was dissolved in methanol and filtered beforepurification by preparative HPLC. ¹H NMR (400 MHz, DMSO-d6) □ 7.81-7.98(m, 3H), 7.53 (d, J=7.28 Hz, 1H), 7.42 (d, J=2.26 Hz, 1H), 7.17-7.25 (m,J=2.38, 8.91 Hz, 1H), 4.34-4.55 (m, 3H), 3.61 (br. s., 2H), 3.05 (br.s., 1H), 2.94 (d, J=5.52 Hz, 1H), 2.63-2.80 (m, 1H), 2.21 (d, J=10.54Hz, 2H), 1.83 (d, J=12.05 Hz, 2H), 1.29-1.43 (m, 2H), 1.19-1.28 (m, 2H),1.02-1.18 (m, 5H), 0.88 (s, 9H) [M+H+] 424.30.

The procedure used for1-((6-((1r,4r)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpyrrolidine-3-carboxylicacid was used with the appropriate amine to make the following:

Example 224N-(3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propyl)methanesulfonamide

¹NMR (400 MHz, DMSO-d₆) □ 7.79-8.01 (m, 3H), 7.48-7.57 (m, 1H), 7.42 (d,J=2.01 Hz, 1H), 7.21 (dd, J=2.26, 9.04 Hz, 1H), 4.34-4.55 (m, 2H),3.92-4.02 (m, 1H), 3.55-3.76 (m, 1H), 2.93-3.12 (m, 2H), 2.77-2.90 (m,1H), 2.21 (d, J=10.54 Hz, 2H), 1.60-1.94 (m, 6H), 1.15-1.43 (m, 3H),1.01-1.14 (m, 1H), 0.88 (s, 9H) [M+1] 447.30

Example 2252-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)octahydrocyclopenta[c]pyrrole-3a-carboxylicacid

¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.98 (m, 3H), 7.49-7.58 (m, 1H), 7.42(d, J=2.01 Hz, 1H), 7.21 (dd, J=2.26, 9.04 Hz, 1H), 4.36-4.54 (m, 3H),3.92-4.00 (m, 1H), 3.57-3.66 (m, 1H), 2.93-3.11 (m, 1H), 2.77-2.89 (m,1H), 2.21 (d, J=10.54 Hz, 2H), 1.72-1.95 (m, 5H), 1.66 (br. s., 2H),1.29-1.44(m, 3H), 1.14-1.28(m, 3H), 1.10 (d, J=11.55 Hz, 1H), 0.88 (s,9H) [M+1+] 450.30

Example 2261-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4,4-dimethylpyrrolidine-3-carboxylicacid

[M+1] 438.30

Example 2271-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-methylpyrrolidine-3-carboxylicacid

1H NMR (400 MHz, DMSO-d6) Shift 7.93 (s, 1H), 7.85 (t, J=9.54 Hz, 2H),7.54 (d, J=8.03 Hz, 1H), 7.41 (d, J=2.01 Hz, 1H), 7.20 (dd, J=2.38, 8.91Hz, 1H), 4.34-4.50 (m, 2H), 2.21 (d, J=9.79 Hz, 2H), 1.82 (d, J=12.30Hz, 2H), 1.29-1.43 (m, 6H), 1.14-1.28 (m, 2H), 1.10 (d, J=11.80 Hz, 1H),0.88 (s, 9H) [M+1] 424.3

Example 2282-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)ethanesulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) d 7.75-7.93 (m, 3H), 7.49 (d, J=8.03 Hz,1H), 7.28 (br. s., 1H), 7.17 (d, J=8.78 Hz, 1H), 4.40 (br. s., 3H), 3.52(d, J=4.02 Hz, 4H) 2.27 (d, J=10.79 Hz, 2H), 1.91 (d, J=11.55 Hz, 2H),1.34-1.50 (m, 2H), 1.27 (d, J=12.55 Hz, 2H), 1.07-1.18 (m, 1H),0.85-0.96 (m, 9H) [M+1] 441.3

Example 2293-(3-(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)oxetan-3-ylamino)propanoicacid

To a mixture of3-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-ylamine (70mg, 0.2 mmol) and Methyl acrylate (21 mg, 0.25 mmol) in Ethanol (1.0 mL,17 mmol) was heated to reflux for 2 d. LCMS monitoring shows 1:1starting material/product, new peak 1.63 min (m/z 440.30 [M+1] 20%).After concentration and HPLC gave product as a solid (18 mg, 20%). 1HNMR (400 MHz, MeOD) d=7.91 (d, J=8.7 Hz, 1 H), 7.87 (s, 1 H), 7.84 (d,J=9.0 Hz, 1 H), 7.38 (dd, J=2.0, 8.6 Hz, 1 H), 7.30 (d, J=2.3 Hz, 1 H),7.20 (dd, J=2.4, 9.0 Hz, 1 H), 5.26 (d, J=8.4 Hz, 2 H), 5.13 (d, J=8.5Hz, 2 H), 4.43-4.31 (m, 1 H), 3.68 (s, 3 H), 3.08 (t, J=6.3 Hz, 2 H),2.70 (t, J=6.3 Hz, 2 H), 2.27 (d, J=10.4 Hz, 2 H), 1.91 (d, J=13.0 Hz, 2H), 1.42 (q, J=12.9 Hz, 2 H), 1.32-1.19 (m, 2H), 1.17-1.04 (m, 1 H),0.91 (s, 9 H).

A solution of3-(3-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-ylamino)-propionicacid methyl ester (18.0 mg, 0.0409 mmol) and Lithium hydroxide (6.41 mg,0.268 mmol) in Tetrahydrofuran (0.6 mL, 8 mmol) and Water (0.2 mL, 9mmol) was stirred at r.t. overnight. LCMS showed a single desiredproduct peak M+Na at m/z 448.20, RT 1.56 min. The solvent wasconcentrated and neutralized with citric acid and concentrated andpurified on HPLC to give product (5.8 mg, 33%), 1H NMR (400 MHz, MeOD)d=7.91 (d, J=8.4 Hz, 1 H), 7.87 (s, 1 H), 7.83 (d, J=8.9 Hz, 1 H), 7.38(d, J=8.2 Hz, 1 H), 7.31 (s, 1 H), 7.20 (d, J=6.8 Hz, 1 H), 5.26 (d,J=7.9 Hz, 2 H), 5.13 (d, J=7.7 Hz, 2 H), 4.43-4.32 (m, 1 H), 3.05 (t,J=5.1 Hz, 2 H), 2.70-2.62 (m, 2 H), 2.27 (d, J=11.2 Hz, 2 H), 1.96-1.85(m, 2 H), 1.50-1.35 (m, 2 H), 1.34-1.18 (m, 2 H), 1.17-1.04 (m, 1 H),0.91 (s, 9 H).

Example 2301-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)ethanone

6-(trans-4-tert-butylcyclohexyloxy)quinoline-2-carbaldehyde (1.63 g,5.23 mmol) was dissolved in Ether (17 mL, 160 mmol). At 0° C., 3.0 M ofMethylmagnesium bromide in diethyl ether (2.62 mL, 7.85 mmol) was added.And after 2 h at r.t., Rochelle's salt was added. The reaction mixturewas stirred and extracted with EtOAc. LCMS shows single peak. LCMSRf=1.47 min, m/z 328.20 ([M+1] 100%), CC with MeOH/DCM gave product(1.73 g, 100%). 1H NMR (400 MHz CHLOROFORM-d) d=8.03 (d, J=8.5 Hz, 1 H),7.97 (d, J=9.1 Hz, 1 H), 7.37 (dd, J=2.8, 9.2 Hz, 1 H), 7.30 (d, J=8.5Hz, 1 H), 7.12 (d, J=2.7 Hz, 1 H), 5.08-4.89 (m, 2 H), 4.33-4.21 (m, 1H), 2.28 (d, J=14.5 Hz, 2 H), 1.92 (d, J=11.1 Hz, 2 H), 1.57 (d, J=6.4Hz, 3 H), 1.53-1.36 (m, 1 H), 1.30-1.01 (m, 4 H), 0.91 (s, 9 H).

1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanol (1.40 g, 4.28mmol) in Methylene chloride (24.5 mL, 382 mmol) was added Dess-Martinperiodinane (3.2 g, 7.6 mmol) and was stirred at room temperature for 1hour. After pass through si gel plug, the solvent was concentrated downto give product as an oil (1.29 g, 93%). LCMS 2.28 min at m/z 326.20([M+1], 100%).

Example 231 methyl1-(1-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)ethyl)azetidine-3-carboxylate

1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (68 mg,0.00021 mol) and Azetidine-3-carboxylic acid methyl ester (23.9 mg,0.000207 mol) was dissolved in Ethanol (0.50 mL, 0.0086 mol) and washeated to reflux for 2 hours. After cooling down to rt, Sodiumcyanoborohydride (32.4 mg, 0.000516 mol) was added and was heated toreflux for 1 hour. After cooling down to rt and concentration, themixture was dissolved into DCM and quenched with NEt₃ and concentrated.The residue was chromatographed with MeOH/CH₂Cl₂ to give product (57.2mg, 65%). LCMS 1.66 min, at m/z 425.30 ([M+1]100%).

Example 2321-(1-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)ethyl)azetidine-3-carboxylicacid

A solution of1-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethyl}-azetidine-3-carboxylicacid methyl ester (57.2 mg, 0.135 mmol) and Lithium hydroxide (20.9 mg,0.874 mmol) in Tetrahydrofuran (2 mL, 20 mmol) and Water (0.5 mL, 30mmol) was stirred at r.t. overnight. LCMS showed a single desiredproduct peak RT 1.60 min M+1 at m/z 413.30, 100%. The solvent wasconcentrated and neutralized with citric acid and concentrated andPurified on HPLC to give product (26.2 mg, 37%). 1H NMR (300 MHz, MeOD)d=8.25 (d, J=8.3 Hz, 1 H), 7.94 (d, J=9.4 Hz, 1 H), 7.42 (d, J=8.3 Hz, 1H), 7.37 (dd, J=2.6, 9.1 Hz, 1 H), 7.28 (d, J=3.0 Hz, 1 H), 4.54-4.43(m, 2 H), 4.42-4.18 (m, 3 H), 3.78-3.59 (m, 1 H), 2.25 (d, J=10.2 Hz, 2H), 1.89 (d, J=11.3 Hz, 2 H), 1.57 (d, J=6.8 Hz, 3 H), 1.51-0.99 (m, 6H), 0.89 (s, 9 H).

Example 233(R,Z)-N-(1-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide

To the solution of1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (0.2227 g,0.0006843 mol) and (s)-(−)-2-Methyl-2-propanesulfinamide (0.0829 g,0.000684 mol) in Methylene chloride (1.4 mL, 0.021 mol) was addedTi(OEt)4 (0.488 mL, 0.00171 mol). The reaction was stirred at roomtemperature for 1 d. The mixture was then cooled to 0° C., added equalvolume brine, filtrate through celite, and extracted with EtOAc. Afterdied over Na₂SO₄, the residue was chromatographed 0-50% EA/HE gaveproduct (132 mg, 45%), LCMS 2.39 min m/z 429.30 ([M+1], 100%),

Example 2342-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)propan-2-amine

To a solution of (S)-2-Methyl-propane-2-sulfinic acid[1-[6-(4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-eth-(E)-ylidene]-amide(132.2 mg, 0.3084 mmol) in Toluene (1.0 mL, 9.4 mmol) at −25° C. underN2, MeMgBr (3M solution in ether, 0.41 mL/g 3, 4 equiv) was addeddropwise. The reaction mixture was stored at ˜−20° C. for 15 minutes.TLC indicated a complete reaction. The reaction mixture was quenched byaddition of saturated NH4Cl at 0° C. The quenched mixture was dilutedwith EtOAc. The aqueous layer was removed. The organic layer was washedwith brine and dried over Na₂SO₄. The drying agent was removed and thedried solution was concentrated under vacuum to a residue, which waschromatographed to give product (76.3 mg, 56%). LCMS 1.82 min m/z 445.30([M+1], 100%).

2-Methyl-propane-2-sulfinic acid{1-[6-(4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethyl}-amide(76.3 mg, 0.172 mmol) in Methanol (1.9 mL, 48 mmol) was added 4.0 M ofHydrogen chloride in 1,4-Dioxane (0.97 mL, 3.9 mmol) and was stirredovernight. After removal of solvent, the residue was dissolved in DMSO,then HPLC give product as a gel (53 mg, 91%). LCMS Rf=1.58 min m/z341.20 ([M+1], 100%), 1H NMR (400 MHz, CHLOROFORM-d) Shift=8.22 (d,J=8.4 Hz, 1 H), 8.00 (d, J=9.2 Hz, 1 H), 7.48 (d, J=8.3 Hz, 1 H), 7.45(dd, J=2.6, 9.2 Hz, 1 H), 7.15 (s, 1 H), 4.38-4.24 (m, 1 H), 2.28 (d,J=10.4 Hz, 2 H), 1.93 (d, J=12.9 Hz, 2 H), 1.88 (s, 6 H), 1.58-1.40 (m,2 H), 1.31-1.01 (m, 3 H), 0.91 (s, 9 H).

Example 2353-(2-(6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)propan-2-ylamino)propanoicacid

To a mixture of1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethylamine(53.0 mg, 0.156 mmol) and Methyl acrylate (0.014 mL, 0.16 mmol;Supplier=Aldrich) in Ethanol (0.32 mL, 5.5 mmol) was heated to refluxfor overnight. LCMS monitoring shows new peak 1.60 min (m/z 427.30[M+1], 20%). After concentration and cc with MeOH/DCM gave product as aoil (35 mg, 53%).

A solution of3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethylamino}-propionicacid methyl ester (36.0 mg, 0.0844 mmol) and Lithium hydroxide (20.2 mg,0.844 mmol) in Tetrahydrofuran (1 mL, 20 mmol) and Water (0.3 mL, 20mmol) was stirred at r.t. overnight. LCMS showed a single desiredproduct peak RT 1.57 min M+1 at m/z 413.30, 100%. The solvent wasconcentrated and neutralized with citric acid and concentrated andPurified on HPLC to give product (20 mg, 57%). 1H NMR (400 MHz,CHLOROFORM-d) d=8.30 (d, J=8.7 Hz, 1 H ), 7.97 (d, J=9.2 Hz, 1 H), 7.59(d, J=8.7 Hz, 1 H), 7.39 (dd, J=2.7, 9.2 Hz, 1 H), 7.30 (d, J=2.5 Hz, 1H ), 4.43-4.28 (m, 1 H ), 3.23 (t, J=6.6 Hz, 2 H), 2.84 (t, J=6.6 Hz, 2H), 2.26 (d, J=10.4 Hz, 2 H), 1.90 (d, J=13.6 Hz, 2 H), 1.79 (s, 6 H),1.49-1.32 (m, 2 H), 1.32-1.17 (m, 2 H), 1.17-1.00 (m, 1 H ), 0.90 (s, 9H).

Example 236 N-(2-Formyl-4-methoxyphenyl)acetamide

5-Methoxy-2-nitro-benzaldehyde (5.00 g, 0.0276 mol), Platinum dioxide(400 mg, 0.002 mol) and Sodium acetate trihydrate (300 mg, 0.002 mol)were placed in a pressure flask, followed by Ethyl acetate (200 mL, 2mol). The reaction mixture was then purged under N₂ at least 3 times,and H₂ was introduced (purged 3 times) and maintained at 52 psi for 3hours. The reaction mixture was then filtered, and cooled to at −20° C.,N,N-Diisopropylethylamine (7.21 mL, 0.0414 mol) was added to thesolution followed by Acetyl chloride (2.36 mL, 0.0331 mol). The reactionmixture was allowed to stir for 2 hours, and quenched with KHCO₃ (sat).Organic layer was separated, and washed with waster, brine and driedover Na₂SO₄. Removal of solvent gave a crude product, which was thenpurified via chromatography (SiO₂, 80 g, 0-100% ethyl acetate/hexanes;4.28 g, 80%). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.25 (s, 3 H) 3.88(s, 3 H) 7.10-7.26 (m, 2 H) 8.69 (d, J=9.06 Hz, 1 H) 9.90 (s, 1 H)10.75-11.04 (m, 1 H). MS (ESI, M+1) 194.10.

Example 237 6-Methoxy-2-methylquinazoline

N-(2-Formyl-4-methoxyphenyl)acetamide (2, 2.50 g, 12.9 mmol) wasdissolved in Ethanol (300 mL, 5000 mmol) and cooled to at −78° C. in ahigh pressure reactor. A solution of NH3 saturated in ethanol was added.The reaction mixture was then heated at 135° C. for 2 hours. Cooled to23° C. and solvent was removed to give a crude product, which was thenpurified via chromatography (SiO₂, 120 g, 0-20% MeOH/DCM; 1.87 g, 83%).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 3 H) 3.97 (s, 3 H) 7.15(d, J=2.51 Hz, 1 H) 7.56 (dd, J=9.04, 2.51 Hz, 1 H) 7.93 (d, J=9.04 Hz,1 H) 9.27 (s, 1 H). MS (ESI, M+1): 175.10.

Example 238 6-Methoxy-2-quinazolinylmethylaldehyde

6-Methoxy-2-methyl-quinazoline (3, 2.50 g, 14.4 mmol) was dissolved in1,4-Dioxane (200 mL, 3000 mmol), followed by Selenium dioxide (11.15 g,100.4 mmol). The reaction mixture was then heated at 90° C. for 12hours. The reaction mixture was filtered. Solvent was removed, and thecrude mixture was purified via chromatography (SiO₂, 80 g, 0-100% ethylacetate/hexanes; 1.85 g, 69%). ¹H NMR (400 MHz, CHLOROFORM-d) □ ppm 4.02(s, 3 H) 7.23-7.31 (m, 1 H) 7.69 (dd, J=9.29, 2.76 Hz, 1 H) 8.16 (d,J=9.29 Hz, 1 H) 9.49 (s, 1 H) 10.23 (s, 1 H). MS (ESI, M+1): 189.10.

Example 239(R)-1-(6-Methoxyquinazolin-2-ylmethyl)pyrrolidine-3-carboxylic acidmethyl ester

6-Methoxy-2-quinazolinylmethylaldehyde (4, 2.40 g, 12.7 mmol) wasdissolved in Methanol (50 mL, 1000 mmol), followed by(R)-Pyrrolidine-3-carboxylic acid methyl ester (3.29 g, 25.5 mmol) at23° C. The reaction mixture was stirred for 30 minutes, then Sodiumcyanoborohydride (1.60 g, 25.5 mmol) was added at −30° C. The reactionmixture was gradually warmed up to 23° C., and stirred for 1 day.Solvent was removed, and the residue was treated with DCM/water. Organiclayer was washed with washer (300×2 mL) and then brine and dried overNa₂SO₄. The product was purified via chromatography (SiO₂, 220 g, 0-10%MeOH/DCM) to give a pure product. 1H NMR (CHLOROFORM-d) δ ppm: 9.23 (s,1H), 7.89 (d, J=9.3 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.07 (br. s., 1H),4.02 (d, J=3.3 Hz, 2H), 3.88 (s, 3H), 3.61 (s, 3H), 3.03-3.25 (m, 2H),2.96 (d, J=4.5 Hz, 1H), 2.68 (t, J=8.2 Hz, 1H), 2.59 (q, J=8.0 Hz, 1H),2.11 (d, 2H). MS (ESI, M+1): 302.10.

Example 240(R)-1-(6-Hydroxy-quinazolin-2-ylmethyl)-pyrrolidine-3-carboxylic acidmethyl eater

(R)-1-(6-Methoxy-quinazolin-2-ylmethyl)-pyrrolidine-3-carboxylic acidmethyl ester (600.00 mg, 1.9911 mmol) was dissolved in Methylenechloride (20 mL, 300 mmol), and cooled to at −78° C. A solution of 1.0 Mof Boron tribromide in Methylene chloride (11.947 mL, 11.947 mmol) wasthen added dropwise. The reaction mixture was then warmed up to 23° C.gradually and then heated at 50° C. for 3 hours. The reaction mixturewas then cooled to −78° C., and cold MeOH (30 mL) was added. The mixturewas then left standing for for 15 hours at 23° C. Solvent was removedunder vacuum, and the residue was treated with K₂CO₃ (sat) to pH˜9, andthen adjusted to pH˜7.5. Extracted with DCM (100×2 mL). Organic layerswere washed with water, brine and dried over Na2SO4. The crude productwas purified via chromatography (SiO₂, 40 g, 0-10% MeOH/DCM) to give apure product (540 mg, 94%). 1H NMR (MeOD) δ ppm: 9.26 (s, 1H), 7.86 (d,J=9.0 Hz, 1H), 7.55 (dd, J=9.2, 2.6 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H),4.00 (d, J=3.0 Hz, 2H), 3.67 (s, 3H), 3.04-3.18 (m, 2H), 2.86 (d, J=2.5Hz, 2H), 2.66-2.77 (m, 1H), 2.10 (s, 2H). MS (ESI, M+1): 288.10.

Example 241(R)-1-{6-[4-(1,1-Dimethylpropyl)cyclohexyloxy]quinazolin-2-ylmethyl}-pyrrolidine-3-carboxylicacid methyl ester

(R)-1-(6-Hydroxyquinazolin-2-ylmethyl)-pyrrolidine-3-carboxylic acidmethyl ester (150.00 mg, 5.2208E-4 mol),cis-4-(1,1-dimethyl)propylcyclohexanol (133.36 mg, 7.8312E-4 mol) andTriphenylphosphine (273.87 mg, 0.0010442 mol) were placed in a 40 mLvial, followed by Toluene (5 mL, 0.04 mol). A solution of in THF (5 mL)was then added dropwise to the reaction mixture at 23° C. The reactionmixture was allowed to stir for 12 hours. The reaction mixture was thenfiltered through a celite pad, and concentrated. The crude mixture waspurified via chromatography (SiO₂, 20 g, 0-35% ethyl acetate/hexanes) togive the desired product (388 mg, 80%). 1H NMR (CHLOROFORM-d) δ ppm:9.25 (s, 1H), 7.93 (d, J=9.3 Hz, 1H), 7.50 (dd, J=9.3, 2.8 Hz, 1H), 7.13(d, 1H), 4.28 (ddd, J=10.9, 6.6, 4.4 Hz, 1H), 3.99-4.16 (m, 2H), 3.67(s, 3H), 3.22-3.34 (m, 1H), 3.16 (dd, J=8.9, 7.4 Hz, 1H), 2.98-3.10 (m,1H), 2.76 (t, J=8.4 Hz, 1H), 2.66 (q, J=8.2 Hz, 1H), 2.26 (d, J=13.1 Hz,2H), 2.06-2.21 (m, 2H), 1.76-1.92 (m, 2H), 3.36-1.55 (m, 2H), 1.29 (q,J=7.6 Hz, 2H), 1.09-1.24 (m, 3H), 0.72-0.90 (m, 9H). MS (ESI, M+1):440.30.

Example 2421-{6-[4-(1,1-Dimethylpropyl)cyclohexyloxyl]quinazolin-2-ylmethyl}pyrrolidine-3-carboxylicacid

1-{6-[4-(1,1-Dimethyl-propyl)-cyclohexyloxy]-quinazolin-2-ylmethyl}-pyrrolidine-3-carboxylicacid methyl ester (229.50 mg, 5.2208E-4 mol) was dissolved in Methanol(5 mL, 0.1 mol) and Tetrahydrofuran (5 mL, 0.06 mol), followed by 2 M ofLithium hydroxide in Water (2 mL, 0.004 mol) at at 23° C. for 10minutes. Excess of solvents were removed under vacuum, and the solidresidue was treated with HCl (2N, 3 mL), and extracted with DCM (20×3mL). The organic layers were dried over Na₂SO₄. Removal of solvent gavea pure product (200 mg, 90%). ¹H NMR (400 MHz, CHLOROPORM-d) δ ppm0.69-0.94 (m, 12 H) 1.13-1.37 (m, 10 H) 1.39-1.59 (m, 2 H) 1.76-1.96 (m,3 H) 2.18-2.37 (m, 2 H) 4.84 (br. s., 1 H) 7.16-7.38 (m, 2 H) 7.55-7.71(m, 1 H) 7.99 (br. s., 1 H) MS (ESI, M+1): 426.30.

The two step procedure used to make1-{6-[4-(1,1-Dimethylpropyl)cyclohexyloxy]quinazolin-2-ylmethyl}pyrrolidine-3-carboxylicacid was utilized with the appropriate alcohol to make the following:

Example 2431-[6-(4-tert-Butylcyclohexyloxy)quinazolin-2-ylmethyl]pyrrolidine-3-carboxylicacid

(88% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 0.88-1.02 (m, 10 H)1.09-1.17 (m, 2 H) 1.17-1.35 (m, 8 H) 1.39-1.61 (m, 2 H) 1.82-2.01 (m, 3H) 2.18-2.37 (m, 2 H) 4.32 (br. s., 0 H) 7.17-7.37 (m, 2 H) 7.60 (br.s., 1 H) 7.99 (br. s., 1 H). MS (ESI, M+1): 412.20.

Example 2441-[6-(4-Cyclopentylcyclohexyloxy)quinazolin-2-ylmethyl]pyrrolidine-3-carboxylicacid

(95% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.00-1.19 (m, 10 H)1.37-1.57 (m, 8 H) 1.57-1.70 (m, 2 H) 1.70-1.87 (m, 2 H) 1.87-2.02 (m, 3H) 2.21 (br. s., 2 H) 4.34 (br. s., 1 H) 7.10-7.34 (m, 1 H) 7.55-7.68(m, 1 H) 7.85-8.07 (m, 2 H) 9.24-9.44 (m, 1 H). MS (ESI, M+1): 424.30.

Example 245 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethanone

To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (5g, 0.01 mol) in 15 mL dry THF stirring at −78° C., was added 2.0 M ofn-Butyllithium in hexane (8.3 mL, 0.017 mol) dropwise. The reaction wasthen stirred at −78° C. for 15 minutes, yellow color results.N-Methoxy-N-methyl-acetamide (1.6 mL, 0.015 mol) in 5 mL THF was thenadded dropwise while the reaction was stirred at −78° C. (rxn wentcolorless upon addition of B). Reaction was then quenched with water andextracted three times with ethyl ether. Organics were dried over MgSO₄,filtered, and concentrated to dryness under reduced pressure. Materialwas purified via column chromatography using a gradient of 0-10%EtOAC/Hexanes (ran neat hexanes for 5 min to elute desbromo SM) on 125 gof SiO₂ to give the title compound as a white solid.

Example 2461-N-Azetidine-3-ethoxycarbonyl-1-ethyl[6-(4-tert-Butyl-cyclohexyloxy)naphthalene

Azetidine-3-carboxylic acid ethyl ester (407.10 mg, 0.0031520 mol) (HClsalt) was combined with Potassium carbonate (653.01 mg, 0.0047249 mol)in Methanol (10 mL, 0.2 mol) and stirred for 15 minutes. The solids wereremoved via filtration. Acetic acid (8.9 uL, 0.00016 mol) was then addedfollowed by 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethanone(511.01 mg, 0.0015750 mol) and Sodium cyanoborohydride (245.55 mg,0.0039074 mol) and the reaction was stirred overnight at RT. Solubilityof SM was very poor. Added Methylene chloride (2.5 mL, 0.039 mol).Mixture became homogeneous after a few minutes. The reaction mixture wasthen heated to 50° C. for 5 hours. The reaction was then left stirringovernight at 50° C. The reaction was then quenched with water andextracted three times with ethyl ether. Organics were combined and driedover MgSO₄. Solids were removed via filtration and 5 g of SiO₂ wasadded. All solvent was then removed and the resulting silica was loadedonto a 24 g column and the reaction was purified using a gradient of0-60% EtOAc/Hexanes and then dried on the highvac to give the titlecompound as a colorless oil. Material will be carried on withoutadditional purification.

Example 2471-Ethyl[6-(4-tert-Butyl-cyclohexyloxy)naphthal-2-yl-N-azetidine-3-carboxylicacid

1-N-Azetidine-3-ethoxycarbonyl-1-ethyl[6-(4-tert-Butyl-cyclohexyloxy)naphthalene(140.1 mg, 0.3307 mmol) was dissolved in Ethanol (2 mL, 40 mmol) thentreated with 1 M of Sodium hydroxide in Water (2 mL, 2 mmol). Themixture was stirred vigorously for 1 hour. LCMS shows about 10%conversion to new more polar spot RT=1.75 min M+1=410. Reaction leftstirring overnight. LCMS indicates no SM remaining. pH was adjust to 3-4with 3 N HCl and reaction was then extracted three times with EtOAc.Organics were combined then dried over MgSO₄, filtered and concentratedto dryness under reduced pressure. Ethyl ether was then added and awhite ppt formed. The ppt was removed via filtration to give a whitesolid that 99% pure by NMR and HPLC. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 0.89 (s, 9 H) 1.02-1.29 (m, 3 H) 1.43 (q, J=11.38 Hz, 2 H) 1.53-1.72(m, 3 H) 1.88 (d, J=11.55 Hz, 2 H) 2.26 (d, J=10.54 Hz, 2 H) 3.18-3.38(m, 1 H) 3.72-3.98 (m, 2 H) 3.98-4.17 (m, 2 H) 4.18-4.33 (m, 1 H) 4.38(br. s., 1 H) 7.05-7.18 (m, 2 H) 7.54 (d, J=8.28 Hz, 1 H) 7.72 (t,J=8.28 Hz, 2 H) 7.83 (br. s., 1 H). MS (ESI, M+1): 410.30.

The same 2 step procedure utilized for1-Ethyl[6(4-tert-Butyl-cyclohexyloxy)naphthal-2-yl-N-azetidine-3-carboxylicacid was used to make the following compound with the appropriate amine.

Example 2483-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethylamino}-propionicacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81 (br. s., 1 H) 0.87 (s, 9 H)0.99-1.14 (m, 1 H) 1.14-1.42 (m, 4 H) 1.64 (d, J=6.78 Hz, 3 H) 1.81 (d,J=12.05 Hz, 2 H) 2.20 (d, J=10.29 Hz, 2 H) 2.57-2.72 (m, 2 H) 2.72-2.88(m, 1 H) 2.97 (br. s., 1 H) 3.32 (br. s., 1 H) 4.30-4.54 (m, 2 H) 7.18(dd, J=8.91, 2.13 Hz, 1 H) 7.35-7.45 (m, 1 H) 7.66 (d, J=7.78 Hz, 1 H)7.79 (d, J=8.78 Hz, 1 H) 7.86 (d, J=8.53 Hz, 1 H) 7.94 (s, 1 H)

Example 249(R)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

(R)-Pyrrolidine-3-carboxylic acid; compound with GENERIC INORGANICNEUTRAL COMPONENT (98 mg, 0.65 mmol) was combined with Potassiumcarbonate (114.44 mg, 0.82203 mmol) in Methanol (5 mL, 100 mmol) andstirred for 15 min. The solids were then removed via filtration and6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (76.7 mg,0.247 mmol) was added to the solution followed by Acetic acid (91 uL,1.6 mmol). Solubility was poor so added Methylene chloride (0.6 mL, 10mmol). Mixture was heated to 55° C. for 30 minutes and then cooled toRT. Sodium cyanoborohydride (0.077630 g, 1.2353 mmol) was then added intwo small portions and the reaction was stirred at RT for 4 hours.Reaction was then treated with 2 additional eqs. of Sodiumcyanoborohydride and heated to 55° C. overnight. Approximately 3 mL ofMeOH was removed on the rotovap and the reaction mixture was treatedwith 2 mL DMSO to dissolve precipitated solids. The reaction was thenpurified directly via prep-HPLC on a 19×150 C18 column using a gradientof 10-100% CH3CN/Water (0.1% TFA) to give the the title compound. 1H NMR(400 MHz, MeOD) Shift=8.01-7.73 (m, 3 H), 7.59-7.43 (m, 1 H), 7.37-7.26(m, 1 H), 7.26-7.12 (m, 1 H), 4.61-4.49 (m, 2 H), 4.48-4.31 (m, 1 H),3.91-3.33 (m, 6 H), 2.60-2.09 (m, 5 H), 2.06-1.81 (m, 3 H), 1.58-1.04(m, 7 H), 1.01-0.80 (m, 9 H). MS (ESI, M+1): 410.30.

The procedure for(R)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-y)methyl]-pyrrolidine-3-carboxylicacid was utilized to prepare the following compounds utilizing theappropriate amine.

Example 250(R)-1-[6-(Bicyclohexyl-4-yloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400 MHz, MeOD) Shift=7.98-7.71 (m, 3 H), 7.59-7.45 (m, 1 H),7.39-7.09 (m, 2 H), 4.69-4.48 (m, 1 H), 4.48-4.32 (m, 1 H), 2.51-2.08(m, 4 H), 1.83 (d, J=7.0 Hz, 7 H), 1.71-1.38 (m, 7 H), 1.12 (none, 6 H).MS (ESI, M+1): 436.30.

Example 251(R)-1-[6-(4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

¹H NMR (400 MHz, METHANOL-d4) δ ppm 1.05-1.34 (m, 7 H) 1.40-1.70 (m, 8H) 1.72-1.88 (m, 2 H) 1.89-2.07 (m, 2 H) 2.23 (d, J=11.04 Hz, 2 H)3.41-3.53 (m, 2 H) 3.53-3.68 (m, 2 H) 4.35-4.48 (m, 1 H) 4.53 (br. s., 2H) 7.20 (dd, J=8.91, 2.38 Hz, 1 H) 7.25-7.34 (m, 1 H) 7.52 (dd, J=8.53,1.51 Hz, 1 H) 7.87 (d, J=8.53 Hz, 1 H) 7.82 (d, J=9.04 Hz, 1 H) 7.93 (s,1 H), MS (ESI, M+1): 422.20.

Example 252(S)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400MHz, MeOD) Shift=7.96-7.92 (m, 2 H), 7.90-7.79 (m, 3 H),7.56-7.49 (m, 1 H), 7.33-7.28 (m, 1 H), 7.24-7.15 (m, 1 H), 4.60-4.47(m, 2 H), 4.44-4.33 (m, 1 H), 3.74-3.34 (m, 4 H), 2.62-2.35 (m, 1 H),2.33-2.20 (m, 2 H), 1.99-1.85 (m, 2 H), 1.53-1.03 (m, 5 H), 0.93 (s, 9H). MS (ESI, M+1): 410.30.

Example 252(R)-1-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.39-1.69 (m, 4 H) 1.99-2.14 (m, 3H) 2.19-2.49 (m, 5 H) 3.34-3.45 (m, 2 H) 3.45-3.70 (m, 2 H) 4.40-4.62(m, 3 H) 7.21 (dd, J=8.91, 2.38 Hz, 1 H) 7.36 (d, J=2.01 Hz, 1 H) 7.53(dd, J=8.53, 1.51 Hz, 1 H) 7.79-7.87 (m, 1 H) 7.89 (d, J=8.28 Hz, 1 H)7.95 (s, 1 H). MS (ESI, M+1): 422.20.

Example 253(R)-1-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.60-1.90 (m, 6 H) 2.17-2.47 (m, 6H) 3.43-3.70 (m, 4 H) 4.54 (br. s., 2 H) 4.83 (br. s., 1 H) 7.27 (dd,J=9.04, 2.26 Hz, 1 H) 7.31-7.38 (m, 1 H) 7.54 (dd, J=8.53, 1.51 Hz, 1 H)7.81-7.92 (m, 2 H) 7.96 (s, 1 H). MS (ESI, M+1): 422.20.

Example 2543-{[6-(4-Cyclopentylcyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-propionicacid

1H NMR (400MHz, DMSO-d6) Shift=7.87-7.61 (m, 3 H), 7.56-7.39 (m, 1 H),7.32-7.20 (m, 1 H), 7.15-6.96 (m, 1 H), 4.39-4.25 (m, 1 H), 4.20-4.04(m, 2 H), 3.20 (s, 2 H), 3.09-2.83 (m, 3 H), 2.71-2.49 (m, 3 H), 2.14-1.90 (m, 3 H), 1.88-1.55 (m, 6 H), 1.16 (none, 10 H).

Example 256(R)-1-[6-(4-tert-Pentyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400 MHz, MeOD) Shift=7.91-7.66 (m, 2 H), 7.43 (s, 1 H), 7.20 (d,J=2.0 Hz, 1 H), 4.43 (s, 1 H), 4.35-4.21 (m, 1 H), 3.72-3.25 (m, 4 H),2.18 (d, J=11.0 Hz, 3 H), 1.75 (br. s., 1 H), 1.38-1.06 (m, 5 H),0.88-0.62 (m, 6 H), MS (ESI, M+1): 424.30.

Example 257(R)-1-[6-(4-Ethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400 MHz, MeOD) Shift=8.04-7.74 (m, 2 H), 7.59-7.43 (m, 1 H),7.37-7.20 (m, 1 H), 4.80-4.72 (m, 1 H), 4.63-4.41 (m, 1 H), 3.80-3.37(m, 4 H), 2.19-1.97 (m, 1 H), 1.79-1.22 (m, 6 H), 0.94 (s, 3 H). MS(ESI, M+1): 382.20.

Example 258(R)-1-[6-(4-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400 MHz, MeOD) Shift=7.92-7.64 (m, 2 H), 7.42 (d, J=7.5 Hz, 1H). 7.19 (d, J=1.8 Hz, 2 H), 4.68-4.57 (m, 0 H), 4.43 (s, 0 H),4.37-4.22 (m, 0 H), 3.74-3.25 (m, 0 H), 2.11 (br. s., 0 H), 1.77 (br.s., 0 H), 1.68-1.43 (m, 0 H), 1.43-0.95 (m, 0 H), 0.82 (t, J=6.3 Hz, 3H). MS (ESI, M+1): 410.30.

Example 259(R)-1-[6-(4-Methoxymethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid

1H NMR (400 MHz, MeOD) Shift=7.70-7.47 (m, 3 H), 7.43-7.29 (m, 1 H),7.23-7.06 (m, 1 H), 7.04-6.89 (m, 1 H), 4.45-4.10 (m, 1 H), 3.79-3.53(m, 2 H), 3.20-3.11 (m, 5 H), 3.01-2.64 (m, 3 H), 2.55-2.32 (m, 2 H),1.79 (s, 7 H), 1.30 (none, 5H). MS (ESI, M+1): 398.10.

Example 260{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-pyrrolidine-3-yl}-aceticacid

1H NMR (400 MHz, MeOD) Shift=8.00-7.77 (m, 5 H), 7.58-7.47 (m, 2 H),7.30 (d, J=1.5 Hz, 2 H), 7.26-7.11 (m, 2 H), 4.50 (s, 3 H), 4.45-4.32(m, 2 H), 3.79-3.38 (m, 5 H), 3.19-2.65 (m, 3 H), 2.65-2.10 (m, 9 H),2.04-1.62 (m, 5 H), 1.52-1.04 (m, 9 H), 0.93 (s, 9 H). MS (ESI, M+1):424.30.

Example 261 5-(4-tert-Butyl-cyclohexyloxy)-2-methyl-benzothiazole

2-Methyl-benzothiazol-5-ol (2.5 g, 0.015 mol),cis-4-thert-butylcyclohexanol (2.84 g, 0.0182 mol), andTriphenylphosphine (4.76 g, 0.0182 mol) were combined in dry Toluene(100 mL, 1 mol) and stirred under nitrogen. Diisopropyl azodicarboxylate(3.6 mL, 0.018 mol) was added dropwise. The reaction was then stirred atRT overnight. Reaction was then concentrated to dryness and then residuewas dissolved in DCM and 5 g of SiO₂ was added. Solvent was removedunder reduced pressure and resulting powder was loaded onto a 40 gcolumn and purified via column chromatography using a gradient of 0-60%EtOAC/Hexanes.

Example 262 5-(4-tert-Butyl-cyclohexyloxy)-benzothiazole-2-aldehyde

Selenium dioxide (180 mg, 1.6 mmol) was combined with 1,4-Dioxane (5 mL,60 mmol) and Water (0.5 mL, 30 mmol) at room, temperature open to theatmosphere. The mixture was then treated with5-(4-tert-Butyl-cyclohexyloxy)-2-methyl-benzothiazole (250 mg, 0.82mmol) and resulting mixture was heated to 65° C. for 2 hours. The heatwas increased to 90° C. and 4 additional eq. of SeO₂ were added.Reaction was stirred for additional 5 hours. LCMS shows nearly completeconversion. Reaction become dark and solids formed in reaction mixture.Reaction was cooled to RT and allowed to stand over night. Solids wereremoved via filtration. Concentrated to dryness then purified directlyvia column chromatography using a gradient of 0-40% Ethylacetate/hexaneto give the title compound as a dark solid.

Example 263(R)-1-[5-(4-tert-Butyl-cyclohexyloxy)-benzothiazol-2-ylmethyl]-pyrrolidine-3-carboxylicacid

(R)-Pyrrolidine-3-carboxylic acid (100 mg, 0.9 mmol) (HCl salt) wascombined with N,N-Diisopropylethylamine (300 uL, 2 mmol) in Methanol(4.0 mL, 98 mmol) and stirred for 15 mjn,5-(4-tert-Butyl-cyclohexyloxy)-benzothiazole-2-carbaldehyde (1.0E2 mg,0.33 mmol) was then added and the mixture was stirred at RT for 30minutes. After 30 minutes the reaction was cooled to 0° C. and Sodiumcyanoborohydride (100 mg, 2 mmol) was added in two portions. Thereaction was then allowed to warm to RT while stirring overnight. Thereaction was then purified directly on the Gilson (10-90% CH₃CN/H₂O(0.1% TFA), 19×150 cm C18, RT=8.6 min) The product was then dried on thehighvac to give the title compound as a white solid. 1H NMR (400 MHz,MeOD) Shift=8.00-7.78 (m, 1 H), 7.69-7.51 (m, 1 H), 7.27-7.05 (m, 1 H),5.09-4.93 (m, 3 H), 4.39-4.21 (m, 1 H), 4.01-3.39 (m, 4 H), 2.65-2.18(m, 3 H), 2.01-1-80 (m, 2 H), 1.53-1.04 (m, 6 H), 0,92 (s, 9 H). MS(ESI. M+1): 417.30,

Example 2641-[6-(4-tert-Butyl-cyclohexyloxy-naphthalen-2-yl]-2,2,2-trifluoro-ethanone

To a solution of 2-Bromo-6-(4-tert-buty)-cyclohexyloxy)-naphthalene (2g, 0.006 mol) in 15 mL dry THF stirring at −78° C., was added dropwise.The reaction was then stirred at −78° C. for 15 minutes, yellow colorresults, 2.2.2-Trifluoro-N-methoxyl13 N-methyl-aceLamide (1.0 mL, 0.0083mol) in 10 mL THF was then added dropwise while the reaction was stirredat −78° C. Once all of the starting material was added reaction thereaction was allowed to warm to room temperature while stirring for 2hours. The Reaction was then quenched with water and extracted threetimes with EtOAc. Organics were dried over MgSO₄, filtered, andconcentrated to dryness under reduced pressure. Crude NMR shows about80% purity (looks like des-bromostarting material). Material waspurified via column chromatography using a gradient of hexanes for onecolumn volume followed by 0-10% EtOAC/Hexanes on 25 g of SiO₂ to givethe title compound as a yellow solid. Material will be carried onwithout additonal purification

Example 2653-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionicacid tert-butyl ester

3-Amino-propionic acid tert-butyl ester (106 mg, 0.727 mmol) wascombined with N,N-Diisopropylethylamine (575 uL, 3.30 mmol) and1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethanone(250 mg, 0.66 mmol) in Methylene chloride (4 mL, 60 mmol). 1 M ofTitanium (IV) chloride in Methylene chloride, (727 uL, 0.727 mmol) wasadded and the mixture was stirred at RT for 5 hours. TLC (20% EtOAC/Hex)shows only traces of SM with new lower Rf spot. The reaction was cooledto 0° C. and Sodium cyanoborohydride (208 mg, 3.30 mmol) in methanol (5mL) was added carefully in two portions (lots of bubbling so removecap.) The reaction was then diluted with 10 mL DCM and the solids wereremoved via filtration. pH was adjust to 10 with 1 M NaOH and thereaction was extracted three times with methylene chloride. Organicswere combined and dried over MgSO₄. Solids were removed via filtrationand the crude reaction was absorbed onto silica (1 g) and purified viacolumn chromatography on 12 g SiO2 using a gradient of 0-15%Ethylacetate/hexane to give material that was impure by NMR and LCMS(compound eluted around 1% EtOAc.) Material was repurified on 24 g ISCOgold column using a long gradient of 0-10% EtOAc/Hex over 30 minutes(desired compound was 2 nd major peak) to give the title compound as acolorless solid.

Example 2663-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionicacid methyl ester

3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionicacid -tert-butyl ester (0.174 g, 0.343 mmol) was dissolved in 4 M ofHydrogen chloride in 1,4-Dioxane (3 mL, 10 mmol) and stirred at RT for2.5 hrs. ALL solvent is removed after purification of the previous step.Reaction was then concentrated to dryness under reduced pressure to givethe title compound which was taken directly to the next step.

Example 2673-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionicacid (BIO-021973)

3-(1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino)-propionicacid methyl ester (164 mg, 0.352 mmol) was dissolved in Ethanol (2 mL,40 mmol) then treated with 1 M of Sodium hydroxide in Water (2 mL, 2mmol). The mixture was stirred vigorously for 1 hour. pH was adjust to3-4 with 6 N HCl and reaction was then extracted three times with EtOAc.Organics were combined then dried over MgSO₄, filtered and concentratedto dryness under reduced pressure. Ethyl ether was then added and awhite ppt formed. The ppt. was removed via filtration to give a whitesolid that 99% pure by NMR and HPLC-traces of ethanol remain. ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 0.83 (s, 9 H) 0.93-1.10 (m, 1 H) 1.11-1.27(m, 2 H) 1.27-1.42 (m, 2 H) 1.73-1.89 (m, 2 H) 2.19 (d, J=10.29 Hz, 2 H)2.67 (t, J=6.53 Hz, 2 H) 3.03-3.18 (m, 2 H) 4.22-4.37 (m, 1 H) 5.33-5.51(m, 1 H) 7.13 (dd, J=8.91, 2.38 Hz, 1 H) 7.21-7.29 (m, 1 H) 7.46 (d,J=8.78 Hz, 1 H) 7.76 (d, J=9.04 Hz, 1 H) 7.85 (d, J=8.78 Hz, 1 H) 7.93(s, 1 H).

Example 268 4-methoxypent-3-en-2-one

A solution of 2,4-pentanedione (100 g, 1 mol), trimethyl orthoformate(106 g, 1 mol), p-TsOH.H₂O (1.16 g, 11.4 mmol) in MeOH (248 mL) washeated at 55° C. for 5 hrs. The mixture was cooled to room temperatureand concentrated. The residue was diluted with CCl₄ (100 mL) and themixture was concentrated again to give the crude product as a dark-brownoil (˜100 g). This residue was subjected to vacuum distillation to givecolorless oil (58.0 g. yield: 50%). bp 32-33° C./3 torr).

Example 268 3-methoxy-1-methylnaphthalene

A solution of t-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was addeddropwise to a suspension of NaNH₂ (84.4 g, 2.2 mmol) in dry THF (480 mL)under nitrogen. The resulting mixture was heated for 2 h at 40-45° C.After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one(68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C.The resulting mixture was stirred at 45° C. for 2 h. A solution ofbromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and themixture was stirred at 55° C. for 6 h. The mixture was allowed to coolto room temperature overnight. The mixture was poured into ice,acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted withEtOAc. The combined organic extracts were concentrated under reducedpressure, and the residue was diluted with acetone (480 mL) and stirredwith conc. HCl solution (24 mL) for 10 min. The mixture was diluted withEtOAc (200 mL) and washed with saturated brine (200 mL). The aqueouslayer was extracted with EtOAc, and the combined organic layers weredried over sodium sulfate, filtered, and concentrated. The residue wassubjected to flash chromatography (700 g silica gel with dry-loading,eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).

Example 269 4-Methylnaphthalen-2-ol

A solution of 4-methylnaphthalen-2-ol compound (22 g, 128 mmol) andn-Bu₄I (52 g, 141 mmol) in dry dichloromethane (650 mL) was added 1.0 Msolution of BCl₃ in dichloromethane (192 mL, 192 mmol) at −78° C. undernitrogen. After 5 min, the solution was allowed to warm to 0° C. andstirred for 1 h. The reaction was quenched with cold water (200 mL) andextracted with dichloromethane. The combined extracts were washed withsaturated brine, dried over sodium sulfate, filtered, and concentrated.The residue was subjected to flash chromatography, eluting with agradient of 10% to 50% EtOAc in heptanes to give brown solid product (16g, yield: 79%).

Example 270 3-(4-tert-butyl-cyclohexyloxy)-1-methyl-naphthalene

A mixture of 4-methyl-naphthalen-2-ol (0.60 g, 3.8 mmol),methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.9 g, 7.6 mmol) andcesium carbonate (3.7 g, 11 mmol) in t-BuOH (10 mL) and 2-butanone (7mL) was heated at 80° C. overnight. After cooled to room temperature,the mixture was treated with water and ether. The organic phase wasdried over MgSO₄, filtered and concentrated. The crude was treated withmethanol to give solid product (0.55 g, yield: 48%). ESI-MS: 297.20(M+H)⁺.

Example 2716-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde(13467-25)

To a mixture of 3-(4-tert-butyl-cyclohexyloxy)-1-methyl-naphthalene (450mg, 1.5 mmol) in 1,2-dichloroethane (9 mL) was added tin tetrachloride(236 uL, 2 mmol) at 0° C. After stirred at 0° C. for 1 hr,dichloromethyl methyl ether (183 uL, 2 mmol) was added. The solution wasstirred at 0° C. for 1 hr and then warmed to room temperature. Themixture was added ice water and stirred for 1 hr, then the dark solutionwas diluted with dichloromethane and washed with water. The organicphase was washed with sodium bicarbonate aqueous, and dried aver MgSO₄.The drying agent was filtered off and the solvent was concentrated todryness to give dark solid product (0.48 g, yield: 97%). ESI-MS: 325.20(M+H)⁺.

Example 272{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester

A solution of6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde (50mg, 0.15 mmol), glycine methyl ester, hydrochloride (27 mg, 0.22 mmol)and N,N-diisopropylethylamine (DIEA) (34 uL) in 1,2-dichloroethane (2mL) was stirred for 1 hour at room temperature. Then sodiumtriacetoxyborohydride (52 mg, 0.25 mmol) was added and stirred for 3hrs. The reaction was diluted with methylene chloride and washed withsaturated sodium bicarbonate aqueous, dried over MgSO₄, filtered, andconcentrated. The crude was purified via silica gel columnchromatography eluted 0-5% MeOH in methylene chloride to give the lightbrown solid (53 mg, yield: 86%). ESI-MS: 420.30 (M+23)⁺.

Example 273{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid

A solution of{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester (40 mg, 0.1 mmol) and lithium hydroxide (16 mg, 0.67mmol) in THF (1.4 mL) and water (0.5) was stirred at 22° C. overnight.After the solvent was concentrated, the residue was treated with water.The resulting solid was filtered and washed with water and purified viaHPLC to give white precipitate as TFA salt (24 mg, yield: 48%). ESI-MS:406.30 (M+23)⁺; ¹H NMR (400 MHz, MeOD) δ=8.075 (d, 1H), 8.065 (d, 1H),7.62 (t, 1H), 7.48 (dd, 1H), 7.38 (s, 1H), 4.78 (s, 2H), 4.52 (m, 1H),3.86 (s, 1H), 2.75 (s, 3H), 2.66 (s, 1H), 2.27 (d, 2H), 1.926 (d, 2H),1.557 (m, 2H), 1.256 (m, 2H), 1.152 (m, 1H), 0.92 (s, 9H).

Example 2744-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-butyricacid

A solution of6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde (50mg, 0.15 mmol) and 4-aminobutanoic acid (20 mg, 0.19 mmol) in ethanol(0.5 mL) was heated to reflux for 2 hrs. The yellow solution was cooledto room temperature and sodium cyanoborohydride (52 mg) was added. Themixture was heated at 50° C. overnight. The crude product was purifiedvia HPLC to give white solid as TFA salt (9 mg, yield: 11%). ESI-MS:412.30 (M+H)⁺; ¹H NMR (400 MHz, MeOD) δ 8.06 (d, 1H), 8.03 (d, 1H),7.58-7.65 (m, 1H), 7.48 (t, J=7.15 Hz, 1H), 7.38 (s, 1H), 4.68 (s, 2H),4.53 (m, 1H), 3.20 (t, 2H), 2.75 (s, 3H), 2.48 (t, J=6.90 Hz, 2H), 2.29(d, J=10.54 Hz, 2H), 2.04 (quin, J=7.34 Hz, 2H), 1.94 (d, 2H), 1.54 (m,2H), 1.28 (m, 2H), 1.16 (m) 1H), 0.93 (s, 9H).

Example 2751-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylicacid methyl ester

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester (40 mg, yield: 51%). ESI-MS: 424.30 (M+H)⁺.

Example 2761-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylicacid

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid. The product was treated with 1N HCl aqueous gave light yellowsolid as HCl salt (30 mg, yield: 86%). ESI-MS: 410.30 (M+H)⁺. ¹H NMR(400 MHz, DMSO) δ 8.10 (d, 1H), 7.97 (d, 1H), 7.55 (t, 1H), 7.47-7.41(m, 2H), 4.60-4.45 (m, 2H), 3.97 (s, 3H), 3.50-3.33 (m, 2H), 2.68 (s,3H), 2.16 (d, 2H), 1.81 (d, 2H), 1.47 (quin, 2H), 1.20 (quin, 2H), 1.09(m, 2H), 0.88 (s, 9H).

Example 2773-{[6-(4-tert-bulyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionicacid ethyl ester

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester (38 mg, yield: 41%), ESI-MS: 426.30 (M+H)⁺.

Example 2783-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionicacid

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid. The crude was purified via HPLC to give white solid as TFA salt(22 mg, yield: 48%). ESI-MS: 398.20 (M+H)⁺. ¹H NMR (400 MHz, CDCl3) □8.89 (s, 2H), 7.95 (d, 1H), 7.91 (d, 1H), 7.52 (m, 1H), 7.41 (t, 1H),7.13 (s, 1H), 4.64 (s, 2H), 4.35 (m, 1H), 3.14 (s, 2H), 2.74-2.65 (m,5H), 2.18 (d, 2H), 1.85 (d, 2H), 1.47 (m, 2H), 1.20-1.02 (m, 3H), 0.88(s, 9H).

Example 2791-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylicacid methyl ester

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester as sticky oil (57 mg, yield: 70%). ESI-MS: 438.30(M+H)⁺.

Example 2801-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid. (36 mg, yield: 69%). ESI-MS: 424.30 (M+H)⁺. ¹H NMR (400 MHz, DMSO)δ 8.14 (d, 1H), 7.88 (d, 1H), 7.44 (t, 1H), 7.35 (m, 1H), 7.27 (s, 1H),4.31 (m, 1H), 3.89 (s, 2H), 2.73 (t, 1H), 2.62 (s, 3H), 2.53 (m, 3H),2.36 (m, 1H), 2.12 (d, 2H), 1.90 (m, 1H), 1.78 (d, 2H), 1.64 (m, 1H),1.36 (m, 2H), 1.20-1.00 (m, 3H), 0.85 (s, 9H).

Example 281 3-(4-tert-butyl-cyclohexyloxy)-1-iodo-naphthalene

A mixture of 4-iodo-naphthalen-2-ol (1.0 g, 3.7 mmol) (See, for example,Australian Journal of Chemistry (1963), 16 401-10. b. Journal of theChemical Society (1943), 468-9, which is incorporated by reference inits entirety), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (1.8g, 7.4 mmol) and cesium carbonate (3.6 g, 11 mmol) in tert-butyl alcohol(10 mL) and 2-butanone (7 mL) was heated in a sealed vial at 100° C. for4 hrs. The mixture was partitioned between water and dichloromethane.The organic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified via a silica gel column elutedwith EtOAc in hexanes from 0 to 30% to give light yellow precipitate(1.10 g, yield: 73%). ESI-MS: 409.10 (M+H)⁺.

Example 2826-(4-tert-butyl-cyclohexyloxy)-8-iodo-naphthalene-2-carbaldehyde

Synthesis was performed as described for6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde(sticky oil, 700 mg, yield: 98%). ESI-MS: 437.10 (M+H)⁺.

Example 2833-{[6-(4-tert-butyl-cyclohexyloxy)-8-iodo-naphthalen-2-ylmethyl]-amino}-propionicacid ethyl ester

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester (light brown solid, 110 mg, yield: 40%). ESI-MS:538.20 (M+H)⁺.

Example 2843-{[6-(4-tert-Butyl-cyclohexyloxy)-8-iodo-naphthalen-2-ylmethyl]-amino}-propionicacid; compound with trifluoro-acetic acid

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid. The crude was purified via HPLC to give white solid as TFA salt (7mg, yield: 30%). ESI-MS: 510.20 (M+H)⁺. ¹H NMR (400 MHz, MeOD) □ 8.13(d, 1H), 8.12 (s, 1H), 8.05 (d, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 4.72(s, 2H), 4.54 (m, 1H), 3.14 (t, 2H), 2.81 (t, 1H), 2.66 (s, 1H), 2.28(d, 2H), 1.94 (d, 2H), 1.60 (m, 2H), 1.30 (m, 2H), 1.16 (m, 1H), 0.93(s, 9H).

Example 285 [6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-acetic acidethyl ester

A solution of 2-bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g,5.5 mmol) in ether (10 mL) under nitrogen was added 1.6 M n-butyllithiumin hexane (4 mL, 6.4 mmol) at 0° C. The solution was stirred for 30 minat 0° C., then treated with copper(I) bromide-dimethyl sulfide complex(0.8 g, 3.9 mmol). After 2 hrs stirring, a solution of ethylbromoacetate (0.7 mL, 6 mmol) in ether (4 mL) was added. The solutionwas stirred at 0° C. for 2 hrs, then warmed to room temperature for 3hrs. The reaction was quenched with 10% HCl aqueous then the insolublewas filtered off. The organic layer was washed with water, sodiumbicarbonate aqueous, dried over MgSO₄, filtered and concentrated. Thecrude was purified via silica gel column eluted with EtOAc in hexanesfrom 0 to 10% to give light yellow solid (0.45 g, yield: 22% yield).ESI-MS: 369.20 (M+H)⁺.

Example 286 2-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethanol

To a solution of [6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]aceticacid ethyl ester (250 mg, 0.68 mmol) in THF (10 mL) was added 1.0 M oflithium tetrahydroaluminate in THF (2 mL, 2 mmol) at 0° C. After stirredat room temperature for 2 hrs, the solution was quenched with ethylacetate (1 mL), then added Rochelle's salt aqueous (1.5 mL). Thesolution was stirred for 1 hr, then extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtered and concentrated. Theresulting crude was purified via a silica gel column eluted with EtOAcin hexanes from 0 to 60% to give white precipitate (0.17 g, yield: 77%).ESI-MS: 327.20 (M+H)⁺.

Example 287[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-acetaldehyde

A solution of 2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-ethanol(170 mg, 0.52 mmol) in methylene chloride (5 mL) was added Dess-Martinperiodinane (0.31 g, 0.73 mmol). After stirred at room temperature for 1hour, the solution was diluted with methylene chloride, washed withsodium thiosulfate aqueous, dried over Na₂SO₄, and concentrated. Thecrude was purified via silica gel column to afford white solid (120 mg,yield: 70%). ESI-MS: 325.20 (M+H)⁺.

Example 2883-{2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-ethylamino}-propionicacid tert-butyl ester

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid methyl ester as white solid (13 mg, yield: 30%). ESI-MS: 454.40(M+H)⁺.

Example 2893-{2-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethylamino}-propionicacid

A solution of3-{2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-ethylamino}-propionicacid tert-butyl ester (13 mg, 0.028 mmol) in 4 M of HCl in 1,4-dioxane(0.50 mL) was stirred at room temperature overnight. After the solventwas concentrated, the crude was purified via HPLC to give white solid (7mg, yield: 49%). ESI-MS: 398.30 (M+H)⁺. ¹H NMR (400 MHz, MeOD) δ 7.73(d, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.33 (dd, 1H), 7.21 (d, 1H), 7.09(dd, 1H), 4.31 (m, 1H), 3.41-3.31 (m, 4H), 3.14 (t, 2H), 2.74 (t, 2H),2.25 (d, 2H), 1.89 (d, 2H), 1.40 (m, 2H), 1.24 (m, 2H), 1.10 (m, 1H),0.90 (s, 9H).

Example 290(R)-1-{2-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-pyrrolidine-3-carboxylicacid

A mixture of (R)-pyrrolidine-3-carboxylic acid, HCl salt (54 mg, 0.35mmol) and potassium carbonate (0.11 g, 0.79 mmol) in methanol (1.4 mL)was stirred for 15 min. The solids were then removed via filtration, andthe filtrate was concentrated. The residue was added[6(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-acetaldehyde (57 mg,0.18 mmol) and sodium triacetoxyborohydride (200 mg, 1 mmol) in1,2-dichloroethane (2 mL) and acetic acid (0.14 mL, 2.4 mmol). Afterheating at 80° C. for 2 hrs, the reaction was diluted withdichloromethane and washed with 5% of citric acid aqueous. The organicphase was concentrated and residue was purified via HPLC to give solidas TFA salt (42 mg, yield: 44%). ESI-MS: 424.30 (M+H)⁺;

Example 291 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

A solution of 1,2,3,4-tetrahydro-isoquinolin-6-ol, HCl salt (2 g, 10mmol) and di-tert-butyldicarbonate (4 g, 18 mmol) in saturated aqueoussodium bicarbonate solution (20 mL) and chloroform (20 mL) was stirredat room temperature overnight. The organic phase was washed with water,dried over MgSO₄, filtered and concentrated. The crude was purified viaa silica gel column eluted with EtOAc in hexanes from 0 to 100% to givedesired product (1.7 g, yield: 65%).

Example 2926-(4-tert-Butyl-cyclohexyloxy)-3.4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

A mixture of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (1.1 g, 4.4 mmol), cesium carbonate (4.3 g, 13 mmol),and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2 g, 8.8mmol). in t-BuOH (12 mL) and 2-butanune (6.0 mL) was heated in a sealedvial at 100° C. overnight. The mixture was partitioned between water andether. The organic phase was washed with water, dried over MgSO₄,filtered and concentrated. The residue was purified via a silica gelcolumn eluted with EtOAc in hexanes from 0 to 30% to give whiteprecipitate (1.0 g, yield: 58%). ¹H NMR (400 MHz, CDCl₃) δ 6.99 (d, 1H),6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H), 3.61 (s, 2H),2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H),1.18-1.00 (m, 3H), 0.87 (s, 9H).

Example 2936-(4-tert-Butyl-cyclohexyloxy)-1,2,3,4-tetrahydro-isoquinoline

A solution of6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (0.89 g, 2.3 mmol) in 4 M of HCl in 1.4-dioxane(10 mL, 40 mmol) and ether (40 mL) was stirred at room temperature for 3hrs to form white precipitate. The solid was collected by filtration togive desired product as HCl salt (0.73 g, yield: 98%), (400 MHz, DMSO) δ7.09 (d, 1H), 6.81 (d, 1H), 6.80 (s, 1H), 4.20 (m, 1H), 4.14 (m, 2H),3.31 (m, 2H), 2.95 (t, 2H), 2.09 (d, 2H), 1.77 (d, 2H), 1.27 (m, 2H),1.20-0.98 (m, 3H), 0.85 (s, 9H).

Example 2943-tert-butoxycarbonylamino-4-[6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-4-oxo-butyricacid tert-butyl ester

A mixture of6-(4-tert-butyl-cyclohexyloxy)-1,2,3,4-tetrahydro-isoquinoline HCl salt,(80 mg, 0.25 mmol), 2-tert-butoxycarbonylamino-succinic acid4-tert-butyl ester (143 mg, 0.49 mmol), triethylamine (41 uL),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg,0.30 mmol) and HOBT monohydrate (10 mg, 0.06 mmol) in DMF (2.0 mL) washeated at 50° C. for 4 hrs. The solution was diluted with ether andwashed with water. The organic phase was dried over MgSO₄, filtered andconcentrated. The residue was purified via a silica gel column elutedwith EtOAc in hexanes from 0 to 20% to give desired product (90 mg,yield: 65%).

Example 2953-amino-4-[6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-4-oxo-butyricacid

A solution of3-tert-butoxycarbonylamino-4-[6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-4-oxo-butyricacid tert-butyl ester (90 mg, 0.16 mmol) in methylene chloride (1.0 mL)and trifluoro acetic acid (0.3 mL) was stirred at room temperatureovernight. After the solvent was concentrated, the residue was purifiedvia HPLC to give white solid as TFA salt (48 mg, yield: 58%). ESI-MS:403.80 (M+H)⁺: 1H NMR (400 MHz, CDCl₃) δ 6.95 (dd, 1H), 6.70 (d, 1H),6.62 (d, 1H), 4.86 (m, 1H), 4.61-4.41 (m, 2H), 4.04 (m, 1H), 3.73-3.51(m, 2H), 2.95-2.75 (m, 3H), 2.70 (m, 1H), 2.14 (d, 2H), 1.83 (d, 2H),1.34 (q, 2H), 1.17-0.99 (m, 3H), 0.86 (s, 9H).

Example 296 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butylester

Synthesis was performed as described for6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(1.1 g, yield: 60%). ESI-MS: 258.10 (M+23)⁺.

Example 2975-(4-Trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indole-1-carboxylic acid-tert-butyl ester

A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butylester (0.33 g, 1.4 mmol), cesium carbonate (0.93 g, 2.8 mmol), andmethanesulfonic acid 4-trifluoromethyl-cyclohexyl ester (0.70 g, 2.8mmol) in t-BuOH (5 mL) and 2-butanone (2.5 mL) was heated in a sealedvial at 100° C. overnight. The mixture was treated with dichloromethaneto form precipitate. The solid was filtered off and the filtrate wasconcentrated. The residue was treated with minimum of amountdichloromethane to form solid during 2 days. The solid was filtered andwashed with ether to give desired product (200 mg, yield: 40%). ESI-MS:408.20 (M+23)⁺.

Example 298 5-(4-Trifluoromethy-cyclohexyloxy)-2,3-dihydro-1H-indole

Synthesis was performed as described for3-amino-4-[6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-4-oxo-butyricacid (130 mg, yield: 88%). ESI-MS: 286.10 (M+H)⁺.

Example 2992-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone

A mixture of 5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-1H-indole(130 mg, 0.46 mmol) and DIEA (103 uL) in methylene chloride (2 mL) wasadded chloroacetyl chloride (47 uL, 0.59 mmol) at room temperature. Theblack solution was stirred for 30 min. The solvent was concentrated togive crude product. The crude was used directly for next step withoutfurther purification (80 mg, yield: 77%). ESI-MS: 362.10 (M+H)⁺.

Example 3003-{2-oxo-2-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethylamino}-propipropionicacid ethyl ester

A mixture of crude2-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone(80 mg, 0.22 mmol), 3-amino-propionic acid ethyl ester as HCl salt (68mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) inacetonitrile (2 mL) was heated to reflux for 4 hrs. The mixture wastreated with water and extracted with ether. The organic phase was driedover MgSO₄, concentrated, and purified via a silica gel column to givedesired product (11 mg, yield 10%). ESI-MS: 443.20 (M+H)⁺.

Example 3013-{2-oxo-2-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethylamino}-propionicacid

Synthesis was performed as described for{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-aceticacid (3.8 mg, yield: 35%). ESI-MS: 415.20 (M+H)⁺. ¹H NMR (400 MHz, MeOD)δ 8.03 (d, 1H), 6.89 (s, 1H), 6.78 (dd, 1H), 4.58 (m, 1H), 4.15-4.03 (m,4H), 3.32 (t, 2H), 2.79 (q, 1H), 2.64 (t, 2H), 2.22 (m, 1H), 2.11 (d,2H), 1.78-1.69 (m, 5H), 1.67-1.56 (m, 2H).

Example 3022-((trans)-4-tert-butylcyclohexyloxy)quinoline-6-carbaldehyde

The mixture of 6-bromo-quinolin-2-ol (500 mg, 0.002 mol),cis-tert-butyl-cyclohexanol (418.5 mg, 0.002678 mol), andtriphenylphosphine (702.4 mg, 0.002678 mol) in toluene (4.754 mL,0.04463 mol) was heated to reflux, and diisopropyl azodicarboxylate(0.5273 mL, 0.002678 mol) was added dropwise and was stirred andrefluxed for 6 hours. The mixture was taken up into DCM and subjected tochromatography purification with EtOAc/hexane (0:100 to 40:60) to giveproduct as a white solid (253 mg, 30%). LCMS Rt=2.82 min (m/z=364.45,M+2, 100% ).

6-Bromo-2-(4-tert-butyl-cyclohexyloxy)-quinoline (115 mg, 0.317 mmol) intetrahydrofuran (2.6 mL, 32 mmol) was added 2.0 M of n-butyllithium incyclohexane (0.4 mL, 0.95 mmol) at −78° C. and was stirred for 15 min.N,N-dimethylformamide (0.12 mL, 1.6 mmol) was added and was stirred for30 minutes. When the reaction completed, 1 M HCl was added and after 5min at −78° C., sat. NaHCO₃ was added and extracted with EtOAc. Theorganic layer was concentrated and purified by silica gel chromatographyusing PE/EA (0-50%) as eluent to give product as a gel (30.6 mg, 31%).LCMS Rt=2.49 min m/z=312.51 ([M+1], 100%).

Example 3033-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propionicacid

A solution of 2-(4-tert-butyl-cyclohexyloxy)-quinoline-6-carbaldehyde(30.6 mg, 0.0983 mmol) and Beta-alanine (8.75 mg, 0.0983 mmol) inethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellowsolution was cooled to rt and sodium cyanoborohydride (7.41 mg, 0.118mmol) was added and was heated to reflux for 1 h. After cooled down tort, citric acid was added and concentrated down. The solid was suspendedin water and filtrate, and the collected solid was washed thoroughlywith water. HPLC purification of the solid give the product (7.5 mg,15%). LCMS Rt=1.60 min m/z=385.49 [M+1]. 1H NMR (400 MHz, MeOD) δ=8.14(d, J=8.8 Hz, 1 H), 7.92 (s, 1 H), 7.88 (d, J=8.7 Hz, 1 H), 7.72 (d,J=10.7 Hz, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 5.29-5.09 (m, 1 H), 4.40 (s, 2H), 3.36 (t, J=5.8 Hz, 2 H), 2.79 (t, J=6.7 Hz, 2 H), 2.30 (d, J=10.9Hz, 2 H), 1.94 (d, J=12.9 Hz, 2 H), 1.55-1.06 (m, 5 H), 0.94 (s, 9 H).

Example 304 methyl 6-(spiro[4.5]decan-8-yloxy)-2-naphthoate

The mixture of spiro[4.5]decan-8-ol (0.915 g, 0.00593 mol),6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL,0.00593 mol) was added dropwise and was stirred and refluxed for 6hours. The mixture was taken up into DCM and subjected to chromatographypurification with EtOAc/hexane (0:100 to 40:60) to give product as awhite solid (1.02 g, 61%). LCMS Rt=2.58 min, m/z=339.34, (M+1), 100%).

Example 305 (6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methanol

6-(Spiro[4.5]dec-8-yloxy)-naphthalen-2-carboxylic acid methyl ester(0.312 g, 0.000922 mol) in tetrahydrofuran (9 mL, 0.1 mol) and 1.0 M oflithium tetrahydroaluminate in tetrahydrofuran (2.76 mL, 0.00276 mol)was added at 0° C. After stirring at rt for 2 h, quench with EtOAc, thenRochele's salt was added and stirred at rt for 1h. Extraction withEtOAc, c/c give the product as a white solid (257.2 mg, 90%). LCMSRt=2.21 min m/z=293.30 ([M−17], 100%).

Example 306 6-(spiro[4.5]decan-8-yloxy)-2-naphthaldehyde

[6-(Spiro[4.5]dec-8-yloxy)-naphthalen-2-yl]-methanol (257.2 mg, 0.8285mmol) in methylene chloride (9 mL, 100 mmol) was added Dess-Martinperiodinane (0.492 g, 1.16 mmol) and was stirred at room temperature for1 hour. After pass through si gel plug, the solvent was concentrateddown to give product as a solid (256 mg, 100%). LCMS Rt=2.44 mmm/z=309.56 ([M+1], 100%).

Example 3073-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methylamino)propanoicacid

A solution of 6-(Spiro[4.5]dec-8-yloxy)-naphthalene-2-carbaldehyde(229.5 mg, 0.7441 mmol) and Beta-alanine (66.3 mg, 0.744 mmol) inethanol (1 mL, 20 mmol) was heated to reflux for 2 h. The yellowsolution was cooled to rt and sodium cyanoborohydride (56.1 mg, 0.893mmol) was added and was heated to reflux for 1 h. After cooled down tort, citric acid was added and concentrated down. Extraction with DCM andprep HPLC gave product as a white solid (88 mg, 31%). LCMS Rt=1.52 minm/z=382.30 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.89 (s, 1 H), 7.83 (d, J=8.5Hz, 1 H), 7.80 (d, J=9.0 Hz, 1 H), 7.48 (dd, J=1.7, 8.5 Hz, 1 H), 7.27(s, 1 H), 7.19 (dd, J=2.3, 8.9 Hz, 1 H), 4.55-4.44 (m, 1 H), 4.35 (s, 2H), 3.36-3.32 (m, 2 H), 2.76 (t, J=6.8 Hz, 2 H), 2.09-1.33 (m, 16 H).

The sequence used to make3-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methylamino)propanoicacid was utilized to synthesize the compound below using the appropriatealcohol as starting material.

Example 3083-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoicacid

A solution of 6-(spiro[5.5]undec-3-yloxy)-naphthalene-2-carbaldehyde(150 mg, 0.46 mmol) and Beta-alanine (41.4 mg, 0.465 mmol) in elhanol(0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution wascooled to rt and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was addedand was heated to reflux for 1 h. After cooled down to rt, citric acidwas added and concentrated down. LCMS shows 1.59 min 396.30 [M+1]. Thesolid was suspended in water and extracted with DCM. CC with prep HPLCgave product (42 mg, 23%). LCMS Rt=1.59 min m/z=396.30 [M+1]. ¹H NMR(400 MHz, MeOD) □=7.89 (br. s., 1 H), 7.86-7.74 (m, 2 H), 7.48 (d, J=8.3Hz, 1 H), 7.26 (br. s., 1 H), 7.19 (br. s., 1 H), 4.48 (br. s., 1 H),4.35 (br. s., 2 H), 3.34 (s, 2 H), 2.76 (s, 2 H), 1.91 (br. s., 2 H),1.68 (br. s., 4 H), 1.55-1.21 (m, 10 H).

Example 309 Further Compounds of Formula (I)

Each of the following additional compounds of formula (I) were preparedanalogously to those described above:

-   4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric    acid;-   (R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic    acid;-   (S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic    acid;-   4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric    acid;-   5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic    acid;-   6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic    acid;-   4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic    acid;-   4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic    acid;-   2-(2-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-2-oxoethylamino)ethylphosphonic    acid; and-   3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-4-oxo-butanoic    acid.

Example 310 Further Compounds of Formula (I)

Each of the following additional compounds of formula (I) are preparedanalogously to those described above:

-   1-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic    acid;-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)sulfonyl)azetidine-3-carboxylic    acid;-   3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)-N-(methylsulfonyl)propionamide;-   5-(2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)ethyl)tetrazole;-   1-hydroxy-2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)ethylphosphonic    acid;-   3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)propylphosphonic    acid;-   3-(((6-(trans-4-tert-butylcyclohexyloxy)quinoxalin-2-yl)methyl)amino)propionic    acid;-   3-(((7-(trans-4-tert-butylcyclohexyloxy)quinolin-3-yl)methyl)amino)propionic    acid;-   3-(((7-(trans-4-tert-butylcyclohexyloxy)cinnolin-3-yl)meLhyl)amino)propionic    acid;-   3-(((5-(trans-4-tert-butylcyclohexyloxy)-1-methylindol-2-yl)methyl)amino)propionic    acid;-   3-(((6-(trans-4-tert-butylcyclohexyloxy)-1-methylindol-2-yl)methyl)amino)piopionic    acid;-   3-(((2-(trans-4-tert-butylcyclohexyloxy)quinazolin-6-yl)methyl)amino)propionic    acid;-   3-(((2-(trans-4-tert-butylcyclohexyloxy)-1-methylindol-6-yl)methyl)amino)propionic    acid;-   3-(((2-(trans-4-tert-butylcyclohexyloxy)-1-methylindol-5-yl)methyl)amino)propionic    acid; and-   3-(((3-(trans-4-tert-butylcyclohexyloxy)-1-methylindol-6-yl)methyl)amino)propionic    acid.

Example 310 Calcium Mobilization

Compounds that are not specific for the S1P₁receptor, e.g., haveS1P₃activity, can cause undesirable side effects. Accordingly, compoundsare tested to identify those that are specific for S1P₁ activity andhave little or no activity, or are antagonists of, S1P₃ activity.Accordingly, the test compounds are tested in a calcium mobilizationassay to determine agonist activity at either the human S1P₁ or humanS1P₃ receptor, and antagonist activity only at the human S1P₃ receptor.The procedure is essentially as described in Davis et al. (2005) Journalof Biological Chemistry, vol. 280, pp. 9833-9841, which is incorporatedby reference in its entirety with the following modifications. Calciummobilization assays were performed in recombinant CHEM cells expressinghuman S1P₁, S1P₂, S1P₃, S1P₄, or S1P₅ purchased from Millipore(Billerica, Mass.). To detect free intracellular calcium, S1P₁, S1P₂,S1P₃, S1P₄, or S1P₅ cells were loaded with FLIPR Calcium 4 dye fromMolecular Devices (Sunnyvale, Calif.). Cells were imaged for calciummobilization using a FLIPR^(TETRA) equipped with a 96-well dispensehead.

Example 311 In Vivo Screening Assays

Measurement of circulating lymphocytes: Compounds are dissolved in 30%HPCD. Mice (C57bl/6 male, 6-10 week-old) are administered 0.5 and 5mg/kg of a compound via oral gavage 30% HPCD is included as a negativecontrol.

Blood is collected from the retro-orbital sinus 5 and 24 hours afterdrug administration under short isoflurane anesthesia. Whole bloodsamples are subjected to hematology analysis. Peripheral lymphocytecounts are determined using an automated analyzer (HEMAVET™ 3700).Subpopulations of peripheral blood lymphocytes are stained byfluorochrome-conjugated specific antibodies and analyzed using afluorescent activating cell sorter (FACSCALIBUR™). Three mice are usedto assess the lymphocyte depletion activity of each compound screened.

Compounds of formula (I) can induce full lymphopenia at times as shortas 4 hours or less to as long as 48 hours or more; for example, 4 to 36hours, or 5 to 24 hours. In some cases, a compound of formula can inducefull lymphopenia at 5 hours and partial lymphopenia at 24 hours. Thedosage required to induce lymphopenia can be in the range of, e.g.,0.001 mg/kg to 100 mg/kg; or 0.01 mg/kg to 10 mg/kg. The dosage can be10 mg/kg or less, such as 5 mg/kg or less, 1 mg/kg or less, or 0.1 mg/kgor less.

Example 312 Assessment of Heart Effect

One reported undesirable effect of an S1P agonist can be, e.g.,bradycardia. Assays are conducted to determine the effect of testcompounds on heart function. The effects of compounds on cardiacfunction are monitored using the ECG genie recording system. ECGs arerecorded in conscious mice (C57bl/6 male, 6-10 week-old) before andafter compound administration. Compounds were administered by oralgavage. Three mice are used to assess heart rate effect of eachcompound. Compounds are found to have little or no effect on heart rateat therapeutic levels.

The abbreviations used herein have their conventional meaning within theclinical, chemical, and biological arts. In the case of anyinconsistencies, the present disclosure, including any definitionstherein will prevail.

The disclosures of each and every patent, patent application, andpublication cited herein are expressly incorporated herein by referencein their entirety into this disclosure. Illustrative embodiments of thisdisclosure are discussed and reference has been made to possiblevariations within the scope of this disclosure. These and othervariations and modifications in the disclosure will be apparent to thoseskilled in the art without departing from the scope of the disclosure,and it should be understood that this disclosure and the claims shownbelow are not limited to the illustrative embodiments set forth herein.

The invention claimed is:
 1. A method for treatment of a pathological condition or symptom in a mammal, wherein the pathological condition is multiple sclerosis, an autoimmune disease, a chronic inflammatory disorder, asthma, an inflammatory neuropathy, arthritis, transplantation rejection, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumour, tumour metastasis, a disease associated with angiogenesis, a vascular disease, neuropathic pain, acute viral disease, an inflammatory bowel condition, insulin or non-insulin dependent diabetes, inhibited cell migration, over-proliferation and secretion of effector cytokines, or lack of secretion of the suppressive cytokine IL-10, comprising administering to said mammal an effective amount of a compound of formula (IIa)

wherein: each of X¹, X², X³, X⁴, X⁵, and X⁶, independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(R^(f)R^(g)), —N(R^(f))SO₂R^(g), —SO₂R^(f), —S(O)₂N(R^(f)R^(g)), —CO₂R^(f), trialkylamino, aryl, or heteroaryl; W is —O—; Cy has the formula:

wherein: Z¹ is —CH₂CH₂—; Z² is —CH₂—; Z³ is a bond; R^(1a) and R^(1b), independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; or R^(1a) and R^(1b), when taken together, are C₂-C₅ alkylene or C₂-C₅ alkenylene; R^(2a) and R^(2b), independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR^(f)R^(g), alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; or R^(1a) and R^(2a), when taken together, are C₁-C₅ alkylene or C₂-C₅ alkenylene; wherein R^(1a), R^(1b), R^(2a), and R^(2b) are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NR^(f)R^(g), or —CO₂R^(f); R³ is -L¹-J-L²-T¹; L¹ is —C(R^(f)R^(g))—; J is —N(R^(f))—; or J is

wherein each of D¹ and D³, independently, is

D² is —[C(R^(f)R^(g))]_(k)—, —[C(R^(f)R^(g))]_(k)—N(R^(f))—, —[C(R^(f)R^(g))]_(k)—O—, —N(R^(f))—, or —N(R^(f))—[(CR^(f)R^(g))]_(k)—; and D⁴ is —[C(R^(f)R^(g))]_(m)—; wherein k is 1 or 2; and m is 0, 1, 2, or 3; provided that no more than 2 ring atoms of D¹-D⁴ are N or O; L² is —C(R^(f)R^(g))—, —C(R^(f)G)-, —C(G)₂-, —C(R^(f)R^(g))—C(R^(f)R^(g))-, —C(R^(f)R^(g))—C(R^(f)G)-, —C(R^(f)R^(g))—C(G)₂-, or a bond; T¹ is —C(O)(OR^(f)), —C(O)N(R^(f))S(O)₂R^(f), tetrazolyl, —S(O)₂OR^(f), —C(O)NHC(O)—R^(f), —Si(O)OH, —B(OH)₂, —N(R^(f))S(O)₂R^(f), —S(O)₂NR^(f), —O—P(O)(OR^(f))OR^(f), or —P(O)₂(OR^(f)); each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl; each R^(f), independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH₂; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CG₃, —OH, —NO₂, alkyl, —OCG₃, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and each R^(g), independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CG₃, —OH, —NO₂, alkyl, —OCG₃, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the compound is of formula (IIa)

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1, wherein the compound is of formula (IIIa, IIIb, IIIc, IIIf, or IIIg)

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein the compound is of formula (IVa), (IVb) or (IVc)

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1, wherein the compound is of formula (VIa), (VIb) or (VIc)

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein T¹ is —C(O)(OR^(f)), —C(O)N(R^(f))S(O₂R^(f)), —O—P(O)(OR^(f))OR^(f), —P(O₂)(OR^(f)), tetrazolyl or —S(O)₂OR^(f).
 7. The method of claim 1, wherein X⁶ is an electron withdrawing group.
 8. The method of claim 1, wherein R^(1a) and R^(2a) are both hydrogen, and R^(1b) is fluoro, chloro, bromo, iodo, methyl, triflurormethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.
 9. The method of claim 1, wherein the compound is of formula (IIa), (IIIa) or (IIIb):

or a pharmaceutically acceptable salt thereof.
 10. The method of claim 9, or a pharmaceutically acceptable salt thereof, wherein:

T¹ is —C(O)(OR^(f)), —C(O)N(R^(f))S(O₂R^(f)), —O—P(O)(O R^(f))OR^(f), —P(O₂)(OR^(f)), tetrazolyl, or —S(O)₂OR^(f).
 11. The method of claim 1, wherein the compound is selected from the group consisting of: 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide; 3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide; 2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid; 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoic acid; 2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) acetic acid; 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid; 3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) propanoic acid; 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid; 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid; 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid; 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid; 3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoic acid; 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-difluoropropanoic acid; 2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid; 2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)acetic acid; 4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid; 4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid; (R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid; (S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid; 4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric acid; 5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic acid; 6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic acid; 4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid; 4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid; 2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)ethylphosphonic acid; 2-(2-(5-(trans-4-tert-butylcyclohexyloxy)indolin-l-yl)-2-oxoethylamino)ethylphosphonic acid; 3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-l-yl)-4-oxo-butanoic acid; 3-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl] -amino } -propionic acid; {[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino } -acetic acid; 4-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl] -amino } -butyric acid; 1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylic acid; and 1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate; or a pharmaceutically acceptable salt thereof.
 12. The method of claim 1, wherein the autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, an inflammatory bowel disease, or multiple sclerosis.
 13. The method of claim 12, wherein the autoimmune disease is multiple sclerosis.
 14. The method of claim 1, further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic. 